Vmat inhibitory compounds

ABSTRACT

Disclosed herein are compounds that bind to the vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions comprising those compounds, and methods of treatment using said compounds and pharmaceutical compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/031,543, filed Jul. 31, 2014, which is hereby incorporated byreference in its entirety.

ACKNOWLEDGEMENT OF GOVERNMENT SUPPORT

This work was supported by the United States Government under the termsof Grant #BX000939, awarded by the United States Department of VeteransAffairs. The United States Government has certain rights in thisinvention.

BACKGROUND

Methamphetamine (MA) is a Schedule II stimulant that has become a highlyabused drug in the US. The National Institute on Drug Abuse (NIDA) hasreported that about 0.3% of the population, (>730,000) has usedmethamphetamine, and that children as young as 12 were among thoseusers. Although there are behavioral programs that report a measure ofsuccess in treating addicts, there are currently no medications approvedfor the treatment of MA addiction. Drugs such as methamphetamine bind tovesicular monoamine transporter 2 (VMAT2), also known as solute carrierfamily 18 member 2 (SLC18A2) and block the vesicular uptake ofneurotransmitters. VMAT2 sequesters neurotransmitters into cytoplasmicvesicles following uptake by plasma membrane transporters on presynapticnerve terminals. In addition, methamphetamine serves as a substrate forVMAT2 and plasma membrane transporters, substituting for theneurotransmitters, and causing their release from vesicular pools. Thesubsequent increase in synaptic neurotransmitter availability is thefoundation for methamphetamine's psychostimulant effects.

VMAT2 is located presynaptically on intracellular storage vesicles andmonoaminergic nerve terminals. VMAT2 has been cloned and is comprised of515 amino acids putatively arranged in 12 interconnected helices. Thetertiary structure is not known. VMAT2 facilitates uptake of dopamine(DA) into vesicles, where it is stored and later released to maintainphysiological concentrations of DA in the synapse. Indeed, without thisstorage capacity, physiological DA demands cannot be met byintracellular synthesis alone. MA, a VMAT2 substrate, causes the releaseof DA from vesicles into the cytosol of presynaptic neurons. It thenaffects the further release of DA into the extracellular space byphysiological neuronal firing or by reverse transport by the DAtransporter (DAT). The result is an increase of DA in the synapse(Dwoskin L P and Crooks P A Biochemical Pharmacology 63, 89 (2002) andSulzer D et al, J Neurosci 15, 4102 (1995); both of which areincorporated by reference herein). This increase is the foundation formethamphetamine's psychostimulant effects which may lead tomethamphetamine addiction (Wimalasena K, Med Res Rev 31, 483-519 (2010);Zheng G et al, AAPS Journal 8, E682 (2006); and Vartak A P et al, J MedChem 52, 7878 (2009); all of which are incorporated by referenceherein).

Reserpine, an alkaloid that inhibits neurotransmitter uptake intovesicles by VMAT2, binds with high affinity but in an essentiallyirreversible fashion to a site that is closely associated with theuptake site. Although it has been used extensively as anantihypertensive agent, reserpine's irreversible binding properties makeit less clinically attractive as a potential pharmacotherapy fortreatment of symptoms associated with MA abuse. Other drugs such astetrabenazine (TBZ) analogues bind with high affinity to a site on theVMAT2 that apparently differs from the reserpine binding site, and theyare under scrutiny as potential medications for the treatment ofsymptoms associated with psychostimulant abuse.

SUMMARY

Currently, there are no approved pharmacotherapies to relieve cravingfor or symptoms associated with methamphetamine (MA) abuse andaddiction. What is needed is a class of compounds that potently blockVMAT2 function, bind weakly to the TBZ binding site, and have lowaffinity for other neurotransmitter receptors and transporters. Suchcompounds would represent a new class of anti-MA treatment medications.

The compounds described herein rely on a novel VMAT2 binding site forfunctional effects and therefore afford an opportunity to constructmolecules that differ in binding and pharmacological profiles from thosealready in exploration as anti-MA pharmacotherapies.

In one aspect, provided herein are compounds of Formula I:

wherein

X is a substituted or unsubstituted 5- or 6-membered aryl or substitutedor unsubstituted 5- or 6-membered heteroaryl,

Z is N or CH,

m is 1, 2, or 3,

Ar is substituted or unsubstituted 5- or 6-membered aryl or substitutedor unsubstituted 5- or 6-membered heteroaryl,

R is H, ethyl ester, isopropyl ester, —C(O)-alkyl (i.e., methyl ketone,ethyl ketone, etc.), or substituted or unsubstituted 5-memberedheteroaryl, and

Y is H, substituted or unsubstituted alkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;

wherein the bond between the carbon atoms bearing Ar and R is a singleor double bond,

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,mixture of stereoisomers, crystal form, isomer, or isotopomer thereof.

In some embodiments, the compound has the structure:

In some embodiments, the bond between the carbon atoms bearing Ar and Ris a single bond, and the groups labeled Ar and R are in an RRconfiguration, an SS configuration, an SR configuration, or an RSconfiguration. In some embodiments, the bond between the carbon atomsbearing Ar and R is a double bond.

In some embodiments, R is —C(O)-alkyl (i.e., methyl ketone, ethylketone, etc.). In some embodiments, R is ethyl ester. In someembodiments, Ar is phenyl, substituted phenyl, pyrrolyl, substitutedpyrrolyl, pyridinyl, substituted pyridinyl, thiophene-yl, substitutedthiophene-yl, or [1,4]-dioxinyl.

In some embodiments, the compound has the structure:

wherein A₁, A₂, A₃, and A₄ are independently H, alkyl, substitutedalkyl, aryl, substituted aryl, halo, alkoxy, haloalkyl, haloalkoxy,ester, keto, hydroxyl, amino, substituted amino, amido, or nitro. Insome embodiments, A₁, A₂, A₃, and A₄ are independently H, methyl, ethyl,isopropyl, [1,4]dioxin-5-yl, fluoro, chloro, trifluoromethyl, amino,dimethylamino, methylamido, nitro, azo, benzyl, 2-phenyl ethyl,pyrrolyl, ethyl ester, 1-hydroxyethyl, hydroxyl, methoxy,trifluoromethoxy, or tert-butoxycarbonylamino. In some embodiments, A₁and A₂ are H, and A₃ and A₄ are independently H, fluoro, ortrifluoromethyl.

In some embodiments, the compound has the structure:

wherein A₃ is halo, and m is 2 or 3. In some embodiments, A₃ is fluoro.

In some embodiments, the compound has the structure:

wherein Y₁ is H, methyl, ethyl, or 2-benzylethyl, wherein Y₂ is H orhalo, and wherein A₃ and A₄ are independently H or halo.

In some embodiments, the compound has the structure:

wherein A₁, A₂, A₃, and A₄ are independently H, halo, or haloalkyl, andwherein Y is H or alkyl. In some embodiments, Y is H, A₁ and A₂ are H,and A₃ and A₄ are independently H, fluoro, or trifluoromethyl.

In another aspect, provided herein is a pharmaceutical compositioncomprising one or more compounds described herein, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptableexcipients.

In another aspect, provided herein is a method of treatingmethamphetamine addiction, the method comprising administering atherapeutically effective amount of a composition described herein to asubject in need thereof.

In another aspect, provided herein is the use of a composition describedherein in treating methamphetamine addiction.

DETAILED DESCRIPTION

I—Definitions

Unless specifically defined otherwise, the technical terms, as usedherein, have their normal meaning as understood in the art. Thefollowing explanations of terms and methods are provided to betterdescribe the present compounds, compositions and methods, and to guidethose of ordinary skill in the art in the practice of the presentdisclosure. It is also to be understood that the terminology used in thedisclosure is for the purpose of describing particular embodiments andexamples only and is not intended to be limiting.

As used herein, the singular terms “a,” “an,” and “the” include pluralreferents unless context clearly indicates otherwise. Similarly, theword “or” is intended to include “and” unless the context clearlyindicates otherwise. Also, as used herein, the term “comprises” means“includes.” Hence “comprising A or B” means including A, B, or A and B.

Variables such as X, R, Q, and Ar, including all subvariables thereof(such as X1, X2, etc.) used throughout the disclosure are the samevariables as previously defined unless stated to the contrary.

“Administration of” and “administering a” compound refers to providing acompound, a prodrug of a compound, or a pharmaceutical compositioncomprising a compound as described herein. The compound or compositioncan be administered by another person to the subject or it can beself-administered by the subject.

The term “alkyl” refers to a branched or unbranched saturatedhydrocarbon group, such as, without limitation, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl,decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A “loweralkyl” group is a saturated branched or unbranched hydrocarbon havingfrom 1 to 6 carbon atoms (C₁₋₆ alkyl). The term “alkyl” also includescycloalkyl. The term “substituted alkyl” refers to an alkyl groupwherein one or more hydrogen atoms are replaced with a substituent suchas, without limitation, halogen, cycloalkyl, alkoxy, amino, hydroxyl,aryl, or carboxyl.

The term “alkylamino” refers to any straight-chain alkylamino,branched-chain alkylamino, cycloalkylamino, cyclic alkylamino,heteroatom-unsubstituted alkylamino, heteroatom-substituted alkylamino,heteroatom-unsubstituted C₁₋₆-alkylamino, and heteroatom-substitutedC₁₋₆-alkylamino. The term “heteroatom-unsubstituted C₁₋₆-alkylamino”refers to a radical, having a single nitrogen atom as the point ofattachment, further having one or two saturated carbon atoms attached tothe nitrogen atom, further having a linear or branched, cyclic oracyclic structure, containing a total of n carbon atoms, all of whichare nonaromatic, 4 or more hydrogen atoms, a total of 1 nitrogen atom,and no additional heteroatoms. For example, a heteroatom-unsubstitutedC₁-C₁₀-alkylamino has 1 to 10 carbon atoms. The term“heteroatom-unsubstituted C₁₋₁₀-alkylamino” includes groups, having thestructure —NHR, in which R is a heteroatom-unsubstituted C₁₋₁₀-alkyl, asthat term is defined above. A heteroatom-unsubstituted alkylamino groupwould include, without limitation, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)₂, —NHCH(CH₂)₂, —NHCH₂CH₂CH₂CH₃, —NHCH(CH₃)CH₂CH₃,—NHCH₂CH(CH₃)₂, —NHC(CH₃)₃, —N(CH₃)₂, —N(CH₃)CH₂CH₃, —N(CH₂CH₃)₂,N-pyrrolidinyl, and N-piperidinyl.

The term “alkoxy” refers to an alkyl group attached to an oxygen atom toform an ether. The term “substituted alkoxy” refers to an alkoxy groupwherein one or more hydrogen atoms are replaced with a substituent suchas, without limitation, halogen, cycloalkyl, alkoxy, amino, hydroxyl,aryl, or carboxyl.

The term “aryl” refers to any carbon-based aromatic group including, butnot limited to, benzene, naphthalene, and phenyl. The term “heteroaryl”is defined as an aromatic group that has at least one heteroatomincorporated within the ring of the aromatic group, including, but notlimited to, oxazole. Examples of heteroatoms include, but are notlimited to, nitrogen, oxygen, sulfur, and phosphorous. The terms“substituted aryl” and “substituted heteroaryl” refer to an aryl groupor heteroaryl group that is substituted with one or more groupsincluding, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide,nitro, amino, ester, ether, ketone, aldehyde, hydroxy, carboxylic acid,cyano, amido, haloalkyl, haloalkoxy, or alkoxy.

“Carboxyl” refers to a —COOH radical. Substituted carboxyl refers to—COOR where R is aliphatic, heteroaliphatic, alkyl, heteroalkyl, or acarboxylic acid or ester. One such substituted carboxyl is an ethylester group which is a —COO—CH₂—CH₃ group.

The term “cycloalkyl” refers to a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,and cyclohexyl. The term “heterocycloalkyl group,” is a cycloalkyl groupas defined above where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as nitrogen, oxygen, sulfur, orphosphorous.

“Derivative” refers to a compound or portion of a compound that isderived from or is theoretically derivable from a parent compound.

The terms “halogenated alkyl” or “haloalkyl group” refer to an alkylgroup as defined above with one or more hydrogen atoms present on thesegroups replaced with a halogen (F, Cl, Br, I). A halogenated etherrefers to a group in which one or more hydrogen atoms present on anether, such as a methyl ether (—OCH₃), is replaced with one or morehalogens. For example, a trifluoromethyl ether has a formula of —OCF₃.

“Heterocycle” means any saturated, unsaturated or aromatic cyclic moietywherein said cyclic moiety contains at least one heteroatom selectedfrom of the group consisting of oxygen (O), sulfur (S), phosphorus (P)and nitrogen (N). Heterocycles may be monocyclic or polycyclic rings.The term “substituted heterocycle” refers to an aryl group that issubstituted with one or more groups including, but not limited to,halogen, alkyl, halogenated C₁₋₆ alkyl, alkoxy, halogenated C₁₋₆ alkoxy,amino, amidino, amido, azido, cyano, guanidino, hydroxyl, nitro,nitroso, urea, OS(O)₂R, OS(O)₂OR, S(O)₂OR, S(O)₀₋₂R, or C(O)OR wherein Rmay be H, alkyl, aryl or any 3 to 10 membered heterocycle; OP(O)OR₁OR₂,P(O)OR₁OR₂, SO₂, NR₁R₂ , NR₁SO₂R₂, C(R₁)NR₂, or C(R₁)NOR₂, wherein R₁and R₂ may be independently H, alkyl, aryl or 3 to 10 memberedheterocycle; NR₁C(O)R₂, NR₁C(O)OR₂, NR₃C(O)NR₂R₁, C(O)NR₁R₂, orOC(O)NR₁R₂, wherein R₁, R₂ and R₃ are each independently selected fromH, alkyl, aryl or 3 to 10 membered heterocycle, or R₁ and R₂ are takentogether with the atoms to which they are attached to form a 3 to 10membered heterocycle.

Exemplary substituents of a heterocycle further include halogen (Br, Cl,I or F), cyano, nitro, oxo, amino, alkyl (e.g., CH₃, C₂H₅, isopropyl,etc.); alkoxy (e.g., OCH₃, OC₂H₅, etc.); halogenated alkyl (e.g., CF₃,CHF₂, etc.); halogenated alkoxy (e.g., OCF₃, CO₂F₅, etc.); COOH,COO-alkyl, CO-alkyl, alkyl-S (e.g., CH₃S, C₂H₅S, etc); halogenatedalkyl-S (e.g., CF₃S, C₂F₅S, etc.); benzyloxy and pyrazolyl I.

Exemplary heterocycles include, but are not limited to, azepinyl,aziridinyl, azetyl, azetidinyl, diazepinyl, dithiadiazinyl,dioxazepinyl, dioxolanyl, dithiazolyl, furanyl, isooxazolyl,isothiazolyl, imidazolyl, morpholinyl, oxetanyl, oxadiazolyl, oxiranyl,oxazinyl, oxazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl,piperidyl, piperidino, pyridyl, pyranyl, pyrazolyl, pyrrolyl,pyrrolidinyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl,thiazolyl, thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl,thiopyranyl, furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl,thienothiazolyl, imidazopyrazolyl, cyclopentapyrazolyl, pyrrolopyrrolyl,thienothienyl, thiadiazolopyrimidinyl, thiazolothiazinyl,thiazolopyrimidinyl, thiazolopyridinyl, oxazolopyrimidinyl,oxazolopyridyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl,imidazopyrazinyl, purinyl, pyrazolopyrimidinyl, imidazopyridinyl,benzimidazolyl, indazolyl, benzoxathiolyl, benzodioxolyl,benzodithiolyl, indolizinyl, indolinyl, isoindolinyl, furopyrimidinyl,furopyridyl, benzofuranyl, isobenzofuranyl, thienopyrimidinyl,thienopyridyl, benzothienyl, cyclopentaoxazinyl, cyclopentafuranyl,benzoxazinyl, benzothiazinyl, quinazolinyl, naphthyridinyl, quinolinyl,isoquinolinyl, benzopyranyl, pyridopyridazinyl and pyridopyrimidinylgroups.

The terms “treatment”, “treat” and “treating” refer to a therapeuticintervention that ameliorates a sign or symptom of a disease orpathological condition after it has begun to develop. As used herein,the terms “treatment”, “treat” and “treating,” with reference to adisease, pathological condition or symptom, also refers to anyobservable beneficial effect of the treatment. The beneficial effect canbe evidenced, for example, by a delayed onset of clinical symptoms ofthe disease in a susceptible subject, a reduction in severity of some orall clinical symptoms of the disease, a slower progression of thedisease, a reduction in the number of relapses of the disease, animprovement in the overall health or well-being of the subject, or byother parameters well known in the art that are specific to theparticular disease.

A “prophylactic” treatment is a treatment administered to a subject whodoes not exhibit signs of a disease or exhibits only early signs, forthe purpose of decreasing the risk of developing pathology.

“Coadminister” means that each of at least two compounds areadministered during a time frame wherein the respective periods ofbiological activity overlap. Thus, the term includes sequential as wellas coextensive administration of two or more drug compounds.

“Optional” or “optionally” means that the subsequently described eventor circumstance can but need not occur, and that the descriptionincludes instances where said event or circumstance occurs and instanceswhere it does not.

The terms “pharmaceutically acceptable salt” or “pharmacologicallyacceptable salt” refers to salts prepared by conventional means, andinclude basic salts of inorganic and organic acids, such as, withoutlimitation, hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid,acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid,fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid,phenylacetic acid, and mandelic acid. “Pharmaceutically acceptablesalts” of the presently disclosed compounds also include those formedfrom cations such as, without limitation, sodium, potassium, aluminum,calcium, lithium, magnesium, zinc, and from bases such as ammonia,ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine,choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine,procaine, N-benzylphenethylamine, diethylamine, piperazine,tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.These salts may be prepared by standard procedures, for example byreaction of the free acid with a suitable organic or inorganic base. Anychemical compound recited in this specification may alternatively beadministered as a pharmaceutically acceptable salt thereof.Pharmaceutically acceptable salts are also inclusive of the free acid,base, and zwitterionic forms. Descriptions of exemplary pharmaceuticallyacceptable salts can be found in Stahl and Wermuth, Eds., Handbook ofPharmaceutical Salts; Properties, Selection and Use, Wiley VCH (2008).When compounds disclosed herein include an acidic function such as acarboxy group, then suitable pharmaceutically acceptable cation pairsfor the carboxy group are well known to those skilled in the art andinclude, without limitation, alkaline, alkaline earth, ammonium, andquaternary ammonium cations. Such salts are known to those of skill inthe art. For additional examples of pharmacologically acceptable salts,see Berge et al, J. Pharm. Sci. 66:1 (1977).

“Saturated or unsaturated” includes substituents saturated withhydrogens, substituents completely unsaturated with hydrogens andsubstituents partially saturated with hydrogens.

The term “subject” includes both human and veterinary subjects.

A “therapeutically effective amount” or refers to a quantity of aspecified agent sufficient to achieve a desired effect in a subjectbeing treated with that agent. Ideally, a therapeutically effectiveamount of an agent is an amount sufficient to inhibit or treat thedisease without causing substantial toxicity in the subject. Thetherapeutically effective amount of an agent will be dependent on thesubject being treated, the severity of the affliction, and the manner ofadministration of the therapeutic composition. Methods of determining atherapeutically effective amount of the disclosed compound sufficient toachieve a desired effect in a subject will be understood by those ofskill in the art in light of this disclosure.

II—The Dopamine Transporter

Presynaptic transporters are the primary mechanism by whichneurotransmitters are deactivated following their physiological releasefrom nerve terminals. MA induces DA transporter (DAT)-associated,Na+-dependent ion currents, suggesting that the drug is a transportersubstrate, i.e., it substitutes for DA and is taken up into the cell bythe DAT (Sonders M S et al, J Neurosci 17, 960-974 (1997); incorporatedby reference herein). Additionally, it is a substrate for the serotonin(5-HT) transporter (SERT) and the norepinephrine (NE) transporter (NET).In rats, DAT activity decreases 1 hour after administration of a singledose of MA but recovers after 24 hours (Fleckenstein A E et al, JPharmacol Exp Ther 282, 834-838 (1997); incorporated by referenceherein). With repeated multiple high doses of MA, DAT activity anddensity are rapidly reduced and recover very slowly (Kokoshka J M et al,Eur J Pharmacol 361, 269-275 (1998).

Amphetamine redistributes the DA transporter (DAT) away from the cellsurface (Saunders C et al, Proc Natl Acad Sci USA 97, 6850-6855 (2000);incorporated by reference herein), a trafficking that is paralleledtemporally by the loss of DAT activity (Kahlig K M et al, J Biol Chem279, 8966-8975 (2004); incorporated by reference herein) and may requireintracellular amphetamine for regulation (Kahlig K M et al, MolPharmacol 70, 542-548 (2006); incorporated by reference herein). Thus,MA interferes with DA deactivation and the physiological function of theDAT.

The spatial and temporal signaling and synaptic and extra-synapticconcentrations of biogenic amine neurotransmitters are regulated in partby the DAT, SERT and NET. The transporters are members of the12-transmembrane domain sodium-chloride dependent transporters, and arethe targets of therapeutics for depression as well as for abused drugssuch as cocaine and MA (Zahniser N R and Doolen S, Pharmacol Ther 92,21-55 (2001); incorporated by reference herein). As reviewed by Torres(Torres G E, J Neurochem 97 Suppl 1, 3-10 (2006); incorporated byreference herein), interactions of the DAT with multiple proteins may beimportant for the assembly, targeting, trafficking or regulation offunction. Evidence supports the model of the DAT functioning as anoligomeric complex, which must be targeted to specialized domains withinneurons. Second messenger systems, including protein kinase A, proteinkinase C, phosphatases, and arachidonic acid regulate activity. Proteinkinase C downregulates DAT by increasing the rate of DAT internalizationand substrates including DA and amphetamine induce internalization ofDAT (Melikian H E, Pharmacol Ther 104, 17-27 (2004); incorporated byreference herein). The DAT interacts with PICK1 (Protein Interactingwith C kinase 1), the focal adhesion protein Hic-5,synaptosome-associated protein 25 kDA (SNAP-25), synuclein, receptor foractivated C kinase-1 (RACK1), syntaxin, protein phosphatase PP2A andPKC-βII.

III—VMAT2: The Vesicular Monoamine Transporter

Once taken up into the cell by the DAT, SERT or NET, MA andneurotransmitters interact with a vesicular monoamine transporter(VMAT2) in the membrane of intracellular vesicles. The VMAT2 is found inmonoaminergic presynaptic neurons, as well as in peripheral tissues. TheVMAT2 pumps cytosolic DA, serotonin (5-HT) and norepinephrine (NE) intoseveral types of vesicles. It functions as an antiporter, with twoprotons being counterported for each biogenic amine molecule; the protongradient is maintained by an ATP-dependent proton pump (reviewed inHenry J P et al, J Exp Biol 196, 251-262 (1994); incorporated byreference herein). Using the proton gradient, the VMAT2 in chromaffincells can develop a monoamine concentration gradient greater than 10,000(Liu Y and Edwards R H, Ann Rev Neurosci 20, 125-156 (1997);incorporated by reference herein). To put this in context, a vesiclewith an internal diameter of 30 nm has a volume of 1.4×10⁻²⁰ liter, andone molecule in this compartment results in a concentration of ˜100 μM(Wallace L J and Connell L E, Synapse 62, 370-378 (2008); incorporatedby reference herein). In axons, VMAT2 is found in synaptic vesicles andlarge dense-core vesicles, while in cell bodies and dendrites the VMAT2is found on tubulovesicular structures (Nirenberg M J et al, 92,8773-8777 (1995); incorporated by reference herein). Because expressionvaries across brain regions, a recombinant cell system is a useful toolfor screening drugs that interact with the VMAT2.

The cloning of VMAT2 (Erickson J D et al, Proc Natl Acad Sci USA 93,5166-5171 (1992); incorporated by reference herein) revealed no sequencehomology with the biogenic amine plasma membrane transporters, but somestructural similarities were identified, including 12 putativetransmembrane domains, glycosylation sites, and several consensussequences for phosphorylation by kinases. The human (h)VMAT2 isabundantly expressed in monoaminergic cell bodies of brain, in thestomach, and in the adrenal medulla. The hVMAT2 has N and C terminaldomains located in the cytoplasm and glycosylation sites facing thevesicle lumen. VMAT2 function is inhibited by the G-protein Gao2 by aninteraction with the first luminal domain (Brunk I et al, J Biol Chem281, 33373-33385 (2006); incorporated by reference herein). Bytransporting neurotransmitter into vesicles, the VMAT2 participates inthe regulation of cytosolic levels and vesicular stores of biogenicamines.

The VMAT2 is neuroprotective; pharmacological blockade of VMAT2 enhances1-methyl-4-phenylpyridinium (MPP+)- and MA-induced DAergic neuronaltoxicity (German D C et al, Neuroscience 101, 1063-1069 (2000);incorporated by reference herein), suggesting that VMAT2 protectsneurons from some exogenous toxins by facilitating sequestration of thetoxins within vesicles. Mice heterozygous for a null VMAT2 mutation aremore sensitive to MA toxicity (Fumagalli F et al, J Neurosci 19,2424-2431. (1999); incorporated by reference herein). Vocci F J andAppel N M, Addiction 102 Suppl 1, 96-106 (2007) (incorporated byreference herein) reviewed possible targets for MA pharmacotherapies andidentified the VMAT2 as having an obligatory role in MA activity. Byinterfering with the ability of neuronal vesicles to transport andaccumulate biogenic amines, MA alters both cytosolic andimpulse-regulated extracellular concentrations of neurotransmitters.

Given the current state of the art, it is unclear how MA gains access tosynaptic vesicles: by diffusion, by transport via the VMAT2, somecombination of the two, or an unknown mechanism. MA is a base with a pKaof 9.8 and is therefore more than 99% protonated at physiological pH.This form is transported by the plasmalemmal transporters. However, MAis highly lipophilic in the neutral state, and can enter cells in theabsence of cell-surface transporters and can enter vesicles from thecytosol across membranes (Sulzer D et al, J Neurosci 15, 4102-4108(1995); incorporated by reference herein). The uncharged MA in thevesicle could then act as a weak base, bind to free protons, anddissipate the pH gradient (Sulzer D and Rayport S, Neuron 5, 797-808(1990); incorporated by reference herein). With an increased pH in thevesicle, more neurotransmitter would be unprotonated and able to leavethe vesicle across the membranes (Cubells J F et al, J Neurosci 14,2260-2271 (1994); incorporated by reference herein).

MA requires the cell-surface transporter to release transmitter to theextracellular space, as confirmed by studies using DAT knockout animals(Jones S R et al, J Neurosci 18, 1979-1985 (1998); incorporated byreference herein). Consistent with this model, the amphetaminederivative fenfluramine causes efflux of neurotransmitter fromchromaffin granules at concentrations above those necessary fordisrupting the intragranule pH (Schuldiner S et al, Mol Pharmacol 44,1227-1231 (1993); incorporated by reference herein).

In contrast, Partilla J S et al, J Pharmacol Exp Ther 319, 237-246(2006); (incorporated by reference herein) concluded that MA's primaryinteraction is as a substrate of the VMAT2 and release is primarily viacarrier-mediated exchange mechanisms. Consistent with this observation,pretreatment with reserpine results in a significant decrease in initialbrain uptake of 2 stereoisomers of [¹¹C]MA (Inoue O et al, Eur J NuclMed 17, 121-126 (1990); incorporated by reference herein).

MA interacts directly with the VMAT2, as evidenced by inhibition of[³H]DTBZ binding, albeit at high concentrations (1.2 mM). As a VMAT2substrate, MA could facilitate release of preloaded neurotransmitter viathe VMAT2 in addition to its action as a weak base.

IV—VMAT2 Inhibitors

One VMAT2 inhibitor, reserpine (Methyl (3β, 16β, 17α, 18β, 20α)-11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban-16-carboxylate)binds with high-affinity to the VMAT2, but the binding is essentiallyirreversible. This results in depletion of biogenic amines, and requiressynthesis of new storage vesicles for recovery of biogenic aminestorage. The reserpine binding site of VMAT2 appears to be associatedwith the neurotransmitter uptake site. In experiments described below,the precursor for [³H]reserpine is synthesized and labeled.

Tetrabenazine, also known as TBZ or Xenazine ((SS,RR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one),onthe other hand, does bind reversibly to the VMAT2, but was developed forthe treatment of schizophrenia half a century ago (Kenney C and JankovicJ, Expert Rev Neurother 6, 7-17 (2006); incorporated by referenceherein). TBZ appears to bind to a different site on the VMAT2 thanreserpine. One model of the binding sites on VMAT2 proposes that thereserpine site has high affinity for substrates and is directed towardthe cytosol. After binding of substrate to the VMAT2, a conformationalchange results in the TBZ-binding conformation (Henry et al, 1998supra). Dihydrotetrabenazine (DTBZ or 2-Hydroxytetrabenazine) waslabeled with a radioligand and used to label VMAT2 herein. DTBZ has ahydroxyl group substituted for the ketone of TBZ and has high affinityfor VMAT2.

Lobeline(2-((2R,6S)-6-((S)-2-Hydroxy-2-phenylethyl)-1-methylpiperidin-2-yl)-1-phenylethanone)a lipophilic alkaloid of Indian tobacco, interacts with both the VMAT2and the DAT, and is being investigated as a possible therapeutic for MAabuse (reviewed in Dwoskin and Crooks, Biochem Pharmacol 63, 89-98(2002). It is quite possible that lobeline and related compounds bind tothe same site that reserpine binds, but currently there are no availableradioligands to label that site. In transfected cells, lobeline has anaffinity of 4.3 μM at VMAT2 and 5.4 μM at the DAT (Miller D K et al, JPharmacol Exp Ther 310, 1035-1045 (2004); incorporated by referenceherein), while in striatal preparations, lobeline has affinity of 0.88μM at VMAT2 (Teng L et al, J Pharmacol Exp Ther 280, 1432-1444 (1997);incorporated by reference herein). In rats trained to lever press forintravenous MA or sucrose, pretreatment with lobeline decreasedresponding to both acutely, however the effect on sucrose showedtolerance over several days, while the lobeline suppression ofMA-responding was robust over 7 days of testing (Harrod S B et al, JPharmacol Exp Ther 298, 172-179 (2001); incorporated by referenceherein).

Ketanserin is primarily considered to be a 5-HT2 receptor antagonist,however it also has high affinity for VMAT2 (reviewed in Zheng G et al,AAPS J 8, E682-692 (2006); incorporated by reference herein).

These drugs will be used throughout the assays described below.

V—Compounds

Disclosed herein are compounds useful for selectively inhibitingfunctional activity of VMAT2. These compounds can bebiodiastereoselective and manifest bioenantioselectivity. Compoundsdisclosed herein have been shown to be potent antagonists of [³H]5HTuptake by the hVMAT2 and their potency is correlated with theirreversible inhibition of [³H]reserpine binding to the hVMAT2. While[³H]DTBZ and [³H]ketanserin are available, DTBZ and ketanserin bind at asite that is not associated with hVMAT2 function.

Disclosed herein are compounds of Formula I

wherein X is a substituted or unsubstituted 5- or 6-membered aryl orsubstituted or unsubstituted 5- or 6-membered heteroaryl,

Z is N or CH,

m is 1, 2, or 3,

Ar is a substituted or unsubstituted 5- or 6-membered aryl or asubstituted or unsubstituted 5- or 6-membered heteroaryl,

R is H, ethyl ester, isopropyl ester, —C(O)-alkyl (i.e., methyl ketone,ethyl ketone, etc.), or substituted or unsubstituted 5-memberedheteroaryl,

Y is H, substituted or unsubstituted alkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;

wherein the bond between the carbon atoms bearing Ar and R is a singleor double bond,

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,mixture of stereoisomers, crystal form, isomer, or isotopomer thereof.

In some embodiments, the bond between the carbon atoms bearing Ar and Ris a single bond, and the groups labeled Ar and R are in an RRconfiguration, an SS configuration, an SR configuration, or an RSconfiguration.

Additionally disclosed are compounds of Formula II:

wherein Y is H, and X, m, Ar, R, and Y are defined as for Formula I. Instill further examples of the compounds of Formula II, R is ethyl ester.

Additionally disclosed are compounds of Formula III:

wherein A₁, A₂, A₃, and A₄, are independently H, alkyl, substitutedalkyl, aryl, substituted aryl, halo, alkoxy, haloalkyl, haloalkoxy,ester, keto, hydroxyl, amino, substituted amino, amido, or nitro. Instill further examples, A₁, A₂, A₃, and A₄ are independently H, methyl,ethyl, isopropyl, [1,4]dioxin-5-yl, fluoro, chloro, trifluoromethyl,amino, dimethylamino, methylamido, nitro, azo, benzyl, 2-phenyl ethyl,pyrrolyl, ethyl ester, keto, 1-hydroxyethyl, hydroxyl, methoxy,trifluoromethoxy, or tert-butoxycarbonylamino.

Additionally disclosed are compounds of Formula IV

wherein A₃ is halo and m is 2 or 3.

Additionally disclosed are compounds of Formula V

wherein Y₁ is H, methyl, ethyl, or 2-benzylethyl, wherein Y₂ is H orhalo, and wherein A₃ and A₄ are independently H or halo.

Additionally disclosed are compounds of Formula VI

wherein A₁, A₂, A₃, and A₄ are independently H, halo, or haloalkyl andwherein Y is H or alkyl.

Certain compounds described herein may be synthesized according toScheme 1, below. Additional compounds described herein may besynthesized using similar methods.

Compounds 1a, 1b and 1c are shown below, and can be interchangeably usedin conditions e above.

The Ar substituents are shown here:

The compounds described herein can be formulated in any excipient abiological system or entity can tolerate to produce pharmaceuticalcompositions. Examples of such excipients include, but are not limitedto, water, aqueous hyaluronic acid, saline, Ringer's solution, dextrosesolution, Hank's solution, and other aqueous physiologically balancedsalt solutions. Nonaqueous vehicles, such as fixed oils, vegetable oilssuch as olive oil and sesame oil, triglycerides, propylene glycol,polyethylene glycol, and injectable organic esters such as ethyl oleatecan also be used. Other useful formulations include suspensionscontaining viscosity enhancing agents, such as sodiumcarboxymethylcellulose, sorbitol, or dextran. Excipients can alsocontain minor amounts of additives, such as substances that enhanceisotonicity and chemical stability. Examples of buffers includephosphate buffer, bicarbonate buffer and Tris buffer, while examples ofpreservatives include thimerosal, cresols, formalin and benzyl alcohol.In certain aspects, the pH can be modified depending upon the mode ofadministration. For example, a formulation having a pH of from about 5to about 6 may be suitable for topical applications. Additionally, thepharmaceutical compositions can include carriers, thickeners, diluents,preservatives, surface active agents and the like in addition to thecompounds described herein.

The pharmaceutical compositions can also include one or more activeingredients used in combination with the compounds described herein. Anyof the compounds described herein can contain combinations of two ormore pharmaceutically-acceptable compounds. Examples of such compoundsinclude, but are not limited to, hypertension agents, anti-emetics,anti-psychotic agents, chlorpromazine, and the like.

The pharmaceutical compositions can be prepared using techniques knownin the art. In one aspect, the composition is prepared by admixing acompound described herein with a pharmaceutically-acceptable compoundand/or carrier. The term “admixing” is defined as mixing the twocomponents together so that there is no chemical reaction or physicalinteraction. The term “admixing” also includes the chemical reaction orphysical interaction between the compound and thepharmaceutically-acceptable compound. Covalent bonding to reactivetherapeutic drugs, e.g., those having nucleophilic groups, can beundertaken on the compound. Second, non-covalent entrapment of apharmacologically active agent in a cross-linked polysaccharide is alsopossible. Third, electrostatic or hydrophobic interactions canfacilitate retention of a pharmaceutically-acceptable compound in thecompounds described herein.

It will be appreciated that the actual preferred amounts of activecompound in a specified case will vary according to the specificcompound being utilized, the particular compositions formulated, themode of application, and the particular situs and subject being treated.Dosages for a given host can be determined using conventionalconsiderations, e.g., by customary comparison of the differentialactivities of the subject compounds and of a known agent, e.g., by meansof an appropriate conventional pharmacological protocol. Physicians andformulators, skilled in the art of determining doses of pharmaceuticalcompounds, can determine dose according to standard recommendations(Physicians Desk Reference, Barnhart Publishing (1999)).

The pharmaceutical compositions described herein can be administered ina number of ways depending on whether local or systemic treatment isdesired, and on the area to be treated. Compositions as described hereincan be administered by different routes, including, without limitation,intravenous, intraperitoneal, subcutaneous, intramuscular, and oraladministration. For oral administration, the compositions can beformulated into oral dosage forms such as, for example, tablets orliquid-filled capsules, or liquid preparations such as syrups, elixirs,or concentrated drops. For injection, compositions can be formulated inisotonic liquid solutions, such as in physiologically compatible buffersor carbohydrate solutions. Administration can be topically (includingophthalmically, rectally, intranasally). Formulations for topicaladministration can include ointments, lotions, creams, gels, drops,suppositories, sprays, liquids and powders. Conventional pharmaceuticalcarriers, aqueous, powder or oily bases, thickeners and the like can benecessary or desirable. Administration can also be directly into thelung by inhalation of an aerosol or dry micronized powder.

Preparations for administration include sterile aqueous or non-aqueoussolutions, suspensions, and emulsions. Examples of non-aqueous carriersinclude water, alcoholic/aqueous solutions, emulsions or suspensions,including saline and buffered media. Parenteral vehicles, if needed forcollateral use of the disclosed compositions and methods, include sodiumchloride solution, Ringer's dextrose, dextrose and sodium chloride,lactated Ringer's, or fixed oils. Intravenous vehicles, if needed forcollateral use of the disclosed compositions and methods, include fluidand nutrient replenishers, electrolyte replenishers (such as those basedon Ringer's dextrose), and the like. Preservatives and other additivescan also be present such as, for example, antimicrobials, anti-oxidants,chelating agents, and inert gases and the like.

Dosing is dependent on severity and responsiveness of the condition tobe treated, but will normally be one or more doses per day, with courseof treatment lasting from several days to several months or until one ofordinary skill in the art determines the delivery should cease. Personsof ordinary skill can easily determine optimum dosages, dosingmethodologies and repetition rates.

EXAMPLES

The following examples are illustrative of disclosed methods. In lightof this disclosure, those of skill in the art will recognize thatvariations of these examples and other examples of the disclosed methodwould be possible without undue experimentation.

Example 1 Biogenic Amine Transporters [¹²⁵I]RTI-55 Binding

Standard methods of assessing [³H]neurotransmitter uptake and[¹²⁵I]RTI-55 binding using HEK cell lines are described in Eshleman etal, J Pharmacol Exp Therap 289, 877-885 (1999), which is incorporated byreference herein and were as follows:

Compounds were weighed and dissolved in DMSO to make a stock solution of10 mM. An initial dilution to 50 μM in assay buffer or water forbinding, or to 1 mM in assay buffer or water for uptake, was made.Subsequent dilutions were made with assay buffer supplemented with DMSO,maintaining a final concentration of 0.1% DMSO. Pipetting was conductedusing a Biomek 2000 robotic workstation.

Cell preparation: Human embryonic kidney cells expressing therecombinant human dopamine transporter (HEK-hDAT), serotonin transporter(HEK-hSERT) or norepinephrine transporter (HEK-hNET) were used. Cellswere grown to 100% confluence on 150 mm diameter tissue culture dishesand served as the tissue source. Cell membranes were prepared asfollows. Medium was poured off the plate, and the plate was washed with10 ml of calcium- and magnesium-free phosphate-buffered saline. Lysisbuffer (10 ml; 2 mM HEPES with 1 mM EDTA) was added. After 10 min, lysedcells were scraped from plates, transferred into centrifuge tubes, andcentrifuged at 30,000×g for 20 min. The supernatant fluid was removed,and the pellet was resuspended in 12-32 ml of sucrose (0.32 M) using aPolytron at setting 7 for 10 sec. The resuspension volume depended onthe density of binding sites within a cell line and was chosen toreflect binding of 10% or less of the total radioactivity.

Assay conditions: Each assay tube contained 50 μl of membranepreparation (about 10-25 μg of protein), 25 μl of unknown or buffer(Krebs-HEPES, pH 7.4; 122 mM NaCl, 2.5 mM CaCl₂, 1.2 mM MgSO₄, 10 μMpargyline, 100 μM tropolone, 0.2% glucose and 0.02% ascorbic acid,buffered with 25 mM HEPES), 25 μl of [¹²⁵I]RTI-55 (40-80 μM finalconcentration) and additional buffer sufficient to bring the finalvolume to 250 μl. Membranes were preincubated with unknowns for 10 minprior to the addition of the [¹²⁵I]RTI-55. The assay tubes wereincubated at 25° C. for 90 min in the dark. Binding was terminated byfiltration over Whatman GF/C filters using a Tomtec Mach II or MACH III96-well cell harvester. Filters were washed for six seconds withice-cold saline. Scintillation fluid was added to each square andradioactivity remaining on the filters was determined using a Wallac μ-or beta-plate reader. Specific binding was defined as the difference inbinding observed in the presence and absence of mazindol (5 μM, HEK-hDATand HEK-hNET) or imipramine (5 μM, HEK-hSERT). Three or more independentcompetition experiments were conducted with duplicate determinations,unless the IC₅₀ value for a drug was greater than 10 μM, and then onlytwo experiments were conducted. GraphPAD Prism was used to analyze thedata, with IC₅₀ values converted to Ki values using the Cheng-Prusoffequation and K_(d) values for [¹²⁵I]RTI-55 of 1.2, 0.98, and 12.1 nM forhDAT, hSERT and hNET, respectively.

Example 2 Biogenic Amine Transporter [³H]Neurotransmitter Uptake

Compounds were tested for potency at inhibition of [³H]DA (dopamine),[³H]NE (norepinephrine) or [³H]5-HT (serotonin) uptake if the Ki valuefor inhibition of [¹²⁵I]RTI-55 binding to hDAT, hNET or hSERT,respectively, was less than 10 μM.

Cell preparation: Human embryonic kidney cells expressing therecombinant human dopamine transporter (HEK-hDAT), serotonin transporter(HEK-hSERT) or norepinephrine transporter (HEK-hNET) were used. Cellswere grown to confluence as described above. The medium was removed, andcells were washed with phosphate buffered saline (PBS) at roomtemperature. Following the addition of 3 ml Krebs Hepes buffer, theplates were warmed in a 25° C. water bath for 5 min. The cells weregently scraped and then triturated with a pipette. Cells from multipleplates were combined. One plate provided enough cells for 48 wells,which was required to generate data on two complete curves for theunknowns.

Uptake inhibition assay conditions: The assay was conducted in 96 1-mlvials. Krebs-HEPES (350 μl) and unknowns (50 μl) were added to vials andplaced in a 25° C. water bath. Specific uptake was defined as thedifference in uptake observed in the presence and absence of mazindol (5μM, HEK-hDAT and HEK-hNET) or imipramine (5 μM, HEK-hSERT). Cells (50μl) were added and preincubated with the unknowns for 10 min. The assaywas initiated by the addition of [³H]DA, [³H]5-HT, or [³H]NE (50 μl, 20nM final concentration). Filtration through Whatman GF/C filterspresoaked in 0.05% polyethylenimine was used to terminate uptake after10 min. The IC₅₀ values were calculated applying the GraphPAD Prismprogram to each curve made up of 6 drug concentrations each. Three ormore independent competition experiments were conducted with triplicatedeterminations, unless the IC₅₀ value is greater than 10 μM, and thenonly two experiments were conducted.

Example 3 VMAT2: [³H]Dihydrotetrabenazine (DHTB) and [³H]KetanserinBinding Assays

Membrane preparation for binding, uptake and release assays usingHEK-hVMAT2 cells: Human embryonic kidney cells expressing the humanvesicular monoamine transporter 2 (HEK-hVMAT2) were used. HEK-hVMAT2cells were grown until confluent. The media was removed from plates,solution A [sucrose (0.32 M) with protease inhibitors] was added to theplate, and cells were scraped from plate. Cells were homogenized with 12strokes of a glass/glass homogenizer. The homogenate was centrifuged at800×g for 10 min. The supernatant was removed and saved, and the pelletwas resuspended, homogenized and centrifuged as above. The supernatantswere combined and centrifuged at 10,000×g for 20 min. The pellet wasresuspended in solution A (0.75 ml). The membranes were osmoticallyshocked by addition of 2.625 ml ice cold water and homogenized by 5strokes of a glass/Teflon homogenizer. The osmolarity was reestablishedwith addition of Tris (338 μl, 0.25M, pH 7.4 at 4° C.), sodium potassiumtartrate (338 μl, 1.0 M), and MgSO₄ (4 μl, 0.9M). The homogenate wascentrifuged at 20,000×g for 20 min.

[³H]DHTB binding assay: The pellet was resuspended in sucrose (0.32M,2.5-5 ml/plate of cells). The membrane preparation from one plate wassufficient to conduct 2-4 drug curves, and depended on the confluency ofthe plate. The binding assay included membrane preparation (50 μl),drug, [³H]DHTB (7-10 nM), and VMAT buffer (2 mM MgSO₄, 25 mM Tris, 100mM NaK tartrate, 0.5mM EDTA, 4 mM KCl, 1.7 mM ascorbic acid, 100 μMtropolone and 10 μM pargyline, pH 7.4 at 25° C.) in a final volume of0.25 ml. Drugs were preincubated with membranes for 10 minutes prior tothe addition of [³H]DHTB, and the assay was incubated in the dark for 60min at room temp. Binding was terminated by filtration over Whatman GF/Cfilters using a Tomtec 96-well cell harvester. Filters were washed forsix seconds with ice-cold saline. Scintillation fluid was added to eachsquare and radioactivity remaining on the filters was determined using aWallac μ- or beta-plate reader. Specific binding was defined as thedifference in binding observed in the presence and absence of Ro4-1284(10 μM, generously supplied by Hoffman LaRoche). Three or moreindependent competition experiments were conducted with duplicatedeterminations. GraphPAD Prism was used to analyze the data, with IC₅₀values converted to K_(i) values using the Cheng-Prusoff equation and aK_(d) value of 38.4 nM for [³H]DHTB.

Example 4 VMAT2: [³H]APQ Binding Assay

Human embryonic kidney cells expressing the human vesicular monoaminetransporter 2 (HEK-hVMAT2) were used. HEK-hVMAT2 cells were grown untilconfluent. The media was removed from plates, ice cold 25 mM Tris-HCl[with protease inhibitors] was added to the plate, and cells werescraped from the plate. Cells were homogenized with a Polytronhomogenizer on setting 6 for 6 seconds. The homogenate was centrifugedat 30,900×g for 20 min. The pellet was osmotically shocked by additionof 2.625 ml ice cold water and homogenized by 5 strokes of aglass/Teflon homogenizer. The osmolarity was reestablished with additionof Tris (338 μl, 0.25M, pH 7.4 at 4° C.), sucrose (0.32M), sodiumpotassium tartrate (338 μl, 1.0 M), and MgSO₄ (4 μl, 0.9M). Thehomogenate is centrifuged at 30,900×g for 20 min.

[³H]APQ binding assay: The membrane preparation from one plate wassufficient to conduct 2-4 drug curves, and depended on the confluency ofthe plate. The binding assay included membrane preparation (50 μl),drug, [³H]APQ (40-50 nM), and VMAT buffer (2 mM MgSO₄, 25 mM Tris, 100mM NaK tartrate, sucrose (0.32 M), 0.5 mM EDTA, 4 mM KCl, 1.7 mMascorbic acid, 100 μM tropolone and 10 μM pargyline, pH 7.4 at 4° C.) ina final volume of 0.25 ml. Drugs were pre-incubated with membranes for10 minutes prior to the addition of [³H]APQ, and the assay was incubatedin the dark for 60 min at 4° C. Binding was terminated by filtrationover Whatman GF/C filters using a Tomtec 96-well cell harvester. Filterswere washed for six seconds with ice-cold Tris-HCl (25 mM).Scintillation fluid was added to each square and radioactivity remainingon the filters was determined using a Wallac μ- or beta-plate reader.Specific binding was defined as the difference in binding observed inthe presence and absence of 10 μM O-7443 (an analog of APQ). Three ormore independent competition experiments were conducted with duplicatedeterminations. GraphPAD Prism was used to analyze the data, with IC₅₀values converted to Ki values using the Cheng-Prusoff equation and aK_(d) value of 93.5 nM for [³H]APQ.

Example 5 Reserpine Binding Assay

Membrane preparation for binding assays using HEK-hVMAT2 cells: Humanembryonic kidney cells expressing the human vesicular monoaminetransporter 2 (HEK-hVMAT2) were used. HEK-hVMAT2 cells were grown untilconfluent. The media was removed from plates, ice cold 25 mM Tris-HCl[with protease inhibitors] was added to the plate, and cells werescraped from the plate. Cells were homogenized with a Polytronhomogenizer on setting 6 for 6 seconds. The homogenate was centrifugedat 30,900×g for 20 min. The pellet was osmotically shocked by additionof 2.625 ml ice cold water and homogenized by 5 strokes of aglass/Teflon homogenizer. The osmolarity was reestablished with additionof Tris (338 μl, 0.25 M, pH 7.4 at 4° C.), sucrose (0.32 M), sodiumpotassium tartrate (338 μl, 1.0 M), and MgSO₄ (4 μl, 0.9M). Thehomogenate was centrifuged at 30,900×g for 20 min.

[³H]Reserpine binding assay: The membrane preparation from two plateswas sufficient to conduct 1 drug curve, and depended on the confluencyof the plate. The binding assay included membrane preparation (100 μl),drug, [³H]Reserpine (7-10 nM), and VMAT buffer (2 mM MgSO₄, 25 mM Tris,100 mM NaK tartrate, sucrose (0.32M), 0.5 mM EDTA, 4 mM KCl, 1.7 mMascorbic acid, 100 μM tropolone and 10 μM pargyline, pH 7.4 at 30° C.)in a final volume of 1 ml. Drugs were pre-incubated with membranes in13×100 borosilicate tubes for 10 minutes prior to the addition of[³H]Reserpine, and the assay was incubated in the dark for 60 min at 30°C. Binding was terminated by addition of 1 μM reserpine at 4° C. for 10minutes. Individual samples were filtered over Whatman GF/C filtersusing a Millipore 12-channel membrane harvester and washed with 12 mlice-cold Tris-HCl (25 mM). Scintillation fluid was added to eachscintillation tube and radioactivity remaining on the filters wasdetermined using a Beckman LS-6500 multi-purpose scintillation counter.Specific binding was defined as the difference in binding observed inthe presence and absence of 1 μM Reserpine. Three or more independentcompetition experiments were conducted with duplicate determinations.GraphPAD Prism was used to analyze the data, with IC₅₀ values convertedto Ki values using the Cheng-Prusoff equation and a K_(d) value of 8.6nM for [³H]Reserpine.

Example 6 h5HT1A Receptors: [³H]8-OH-DPAT Binding

Human embryonic kidney cells expressing the human 5HT1A receptor(HEK-h5HT1A) were used. The cells were grown to confluence in DMEMcontaining 10% FetalClone® (abbreviated as FC—source: HyClone), 0.05%penicillin-streptomycin (pen-strep), and 300 μg/mL of Geneticin (G418).The cells were scraped from 150 mm plates into phosphate-buffered salineand centrifuged at 270×g, 1200 rpm, for 10 minutes. The cell pellet washomogenized in 50 mM Tris-HCl (pH 7.7) with a Polytron, and centrifugedat 27,000×g. The homogenization and centrifugation were repeated to washany remaining 5HT from the growth media. The final pellet wasresuspended at 0.5 mg protein/mL in assay buffer (25 mM Tris-HCl, pH7.4, containing 100 μM ascorbic acid and 10 μM pargyline). The assay wasperformed in duplicate in a 96-well plate. Serial dilutions of testcompounds were made using the Biomek 2000 robotics system. The reactionmixture contained unknown compound, 100 μl of cell homogenate (0.05 mgprotein/well) and 100 μl of [³H]8-OH-DPAT (0.5 nM final concentration,170 Ci/mmol, Perkin Elmer) in a final volume of 1 ml. Nonspecificbinding was determined with 1.0 μM dihydroergotamine. The plates wereincubated at room temperature for 60 minutes and then filtered throughpolyethylenimine-soaked (0.05%) “A” filtermats on a Tomtec cellharvester. The filters were washed with cold 50 mM Tris buffer (pH 7.7)for 6 sec, dried, spotted with scintillation cocktail, and counted for 2minutes after a 4 hour delay on a Wallac Betaplate 1205 liquidscintillation counter. IC₅₀ values were calculated with GraphPad Prism,and IC₅₀ values were converted to Ki values using the Cheng-Prusoffcorrection and a K_(d) value of 5.02 nM for [³H]8-OH-DPAT.

Example 7 h5HT2A and 2C Receptors: [¹²⁵I]DOI Binding Assays

The method was adapted from A R Knight et al, Naunyn-Schmeideberg's ArchPharmacol 370, 114-123 (2004).

Method: Human embryonic kidney cells expressing the human 5HT2A receptor(HEK-h5HT2A) or human 5HT2C receptor (HEK-h5HT2C) were used. The cellswere grown until confluent on 15 cm plates. Media was removed, cellswere washed with phosphate-buffered saline (PBS), scraped into 2 ml PBSand frozen at −20° C. until needed. Cell suspension was thawed, 10 mlassay buffer (50 mM Tris, pH 7.4 at 37° C., with 0.1% ascorbic acid and5 mM CaCl₂) was added per plate of cells, and polytronned at setting 6for 5 sec. The homogenate was centrifuged at 15,500 rpm for 20 min. Tominimize the residual 5HT concentration, the pellet was resuspended inbuffer, polytronned, and centrifuged as above. The final pellet wasresuspended in 2 ml buffer/plate of cells.

The binding assay included 50 μl drug, 5HT or buffer, 50 μl cellhomogenate, 50 μl [¹²⁵I]DOI (˜0.1 nM) and buffer in a final volume of250 μl. Specific binding was defined as the difference between totalbinding and binding in the presence of 10 μM 5HT. The reaction wasincubated for 1 hour at 37° C., and terminated by filtration throughWallac A filtermats presoaked in 0.05% polyethylenimine using a Tomtec96-well harvester. Radioactivity remaining on filters was counted in aWallac betaplate reader. IC₅₀ values were calculated using GraphPadPrism. IC₅₀ values were converted using the Cheng-Prusoff equation. Thedensity of 5HT2A receptors was 612±19 fmol/mg protein. The density of5HT2C receptors was 900±170 fmol/mg protein. The K_(d) values used inthe equations were 3.624 nM and 4.18 nM for [¹²⁵I] DOI at 5HT2A and5HT2C receptors, respectively.

Example 8 Ketanserin Analogs

These compounds showed poor blocking of radioligand binding torecombinant hVMAT2 or/and manifested substantial potency at blockingradioligand binding to the 5-HT2a receptor.

TABLE 1 Binding of Ketanserin Analogs 5-HT1A hVMAT2 hVMAT2 [³H] 8-OH5-HT2A [³H]DTBZ 5HT Uptake DP AT [¹²⁵I]DOI Ki (nM) ± IC₅₀ (nM) ± Ki(nM)± Ki (nM) ± R₁ R₂ SEM SEM SEM SEM H H 119 ± 3  142 ± 23  >3 μM 24.7 ±7.6 Br H   >3 μM >2 μM >2 μM  0.80 ± 0.24 H α-CO₂Et 1166 ± 314 60 ±10 >10 μM 37.3 ± 8.5 H α/β-CH₃ 276 ± 24 333 ± 106 >10 μM  45.9 ± 12.4 Hα >6.4 μM >7.3 μM   >5 μM 19.8 ± 5.8

New compounds comprising a direct link between the piperidine and 4-arylgroup were then generated to alter the molecular topology of themolecule. A robust synthesis was developed and 5 new compounds wereprepared as shown in Table 3.

Example 9 APQ Analogs

Preliminary data on these compounds indicated that a novel VMAT2selective inhibitor could be obtained. All the compounds inhibiteduptake of [³H]5HT with the compound having a double bond at 3, 4 and ahydrogen at R₁ being especially potent. The compound having a cis ethylester at R₁ and a single bond at 3, 4 was also quite potent atinhibiting uptake, but showed no binding to the 5-HT2A receptor. Thiscan be compared to the compound with a trans ethyl ester that inhibited5HT uptake, but bound to the 5-HT2A receptor. Data are summarized inTable 2.

TABLE 2 Summary of Initial APQ Analog Data 5-HT1A hVMAT2 hVMAT2 [³H]8-OH 5-HT2A [³H]DTBZ 5HT Uptake DPAT [¹²⁵I]DOI 3,4- Ki (nM) ± IC₅₀ (nM)± Ki(nM) ± Ki (nM) ± R₁ bond SEM SEM SEM SEM H ene 821 ± 197 3.9 ± 0.5197 ± 15 139 ± 27 H single 752 ± 372  10 ± 2.6 >4.2 μM 126 ± 39 CO₂-Etene 874 ± 276 66 ± 15 >6.3  81 ± 26 β-CO₂-Et single >9 μM  17 ±4.4 >10.0 μM >10.0 μM α-CO₂-Et single >1.2 μM   74 ± 16 >10 μM 37.3 ±8.5

Example 10 Binding of Compounds of Formula Ill:

Formula Ill

TABLE 3 hVMAT2 5-HT1A hVMAT2 5HT [3H] 8-OH 5-HT2A [³H]DTBZ Uptake DPAT[125I]DOI A₁ A₂ A₃ A₄ Ki (nM) ± SEM IC₅₀ (nM) ± SEM Ki (nM) ± SEM Ki(nM) ± SEM H H H H 1166 ± 314  17 ± 4.4 >10 μM 37.3 ± 8.5 H H F H  >7 μM32 ± 8   >9 μM  >2 μM H H H F >10 μM 63 ± 10 — — F H H H >10 μM 28 ± 12— — H H F F >10 μM 100 ± 19  — — H H Cl H >10 μM 49 ± 1  — — H H H Cl >9 μM 34 ± 8  — — H H Cl Cl — — — — H H H OCH₃ >10 μM 180 ± 54  — — H HOCH₃ OCH₃ >10 μM >3 μM H H NO₂ H >10 μM 758 ± 165 — — H H NH₂ H >10 μM2155 ± 237  — — N(CH₃)₂ H H H  >6 μM >2 μM — — H H H N(CH₃)₂ >10 μM >5μM >10 μM >10 μM H H H N₃  >7 μM 74 ± 11 — — CF₃ H H H — 328 ± 38  — — HH CF₃ H >10 μM 416 ± 43  >10 μM >10 μM H H H CF₃ >10 μM 166 ± 6  >10μM >10 μM CH₃ H H H  >5 μM 31 ± 3  H H CH₃ H  >9 μM 313 ± 54  >10 μM >10μM H H H CH₃ >6200 53 ± 10 — — H H Benzyl H >10 μM >10 μM  >10 μM >10 μMH H Isopropyl H 1625 ± 107 684 ± 249 — — H H OCH₃ H >10 μM 36 ± 11 — — HH CH₂CH₃ H >8400 906 ± 14  — — H H COOEt H >10 μM >10 μM  >10 μM >10 μMH H OCF₃ H  >5 μM — — — H H OH OH — 333 ± 85  — — H H CHOHCH₃ H  >9μM >8 μM >10 μM >10 μM H H CONH₂ H  >3 μM >10 μM  — —

Example 11 Binding of Optical Activity Variants of Formula Ill

The compound of Formula Ill above with A₁=H, A₂=H, A₃=F, and A₄=H isdesignated Compound 5d. 5d was separated into purified + and − variants.Results are shown in Table 4.

TABLE 4 hVMAT2 hVMAT2 5-HT1A 5-HT2A [³H]DTBZ 5HT Uptake [³H] 8-OH[125I]DOI Ki IC₅₀ DPAT Ki Ki Compound (nM) ± SEM (nM) ± SEM (nM) ± SEM(nM) ± SEM 5d (+/−)  >7 μM 32 ± 8    >9 μM  >2 μM 5d+ >10 μM 16 ±3.3 >10 μM >10 μM 5d− >10 μM 52.9 ± 10.5  >10 μM >10 μM

Example 12 Binding of Compounds of Formula IV

The following is an example of a compound of Formula IV wherein A₃ is F.Binding of variants in the alkyl linker is described in Table 5.

TABLE 5 5-HT1A hVMAT2 hVMAT2 [³H] 8-OH 5-HT2A [³H]DTBZ 5HT Uptake DPAT[¹²⁵I]DOI Ki (nM) ± IC₅₀ (nM) ± Ki(nM) ± Ki (nM) ± n SEM SEM SEM SEM1 >7 μM 32 ± 8 >9 μM >2 μM 2 >10 μM 43 ± 4 >10 μM — 3 >10 μM 133 ± 52 ——

Example 13 Binding of Compounds of Formula V

Compounds of Formula V were synthesized. Binding of variants in A₁ areshown in Table 6 below.

TABLE 6 5-HT1A hVMAT2 hVMAT2 [³H] 8-OH 5-HT2A [³H]DTBZ 5HT Uptake DPAT[¹²⁵I]DOI Ki (nM) ± IC₅₀ (nM) ± Ki(nM) ± Ki (nM) ± A₁ SEM SEM SEM SEMH >10 μM  60 ± 26 >9 μM >9 μM CH₃ >8 μM 312 ± 18 — —

Example 14 Binding of Compounds of Formula VI

Binding of compounds with the structure of Formula VI wherein A₁ and A₂are both H is shown in Table 7 below.

TABLE 7 5-HT1A hVMAT2 hVMAT2 [³H] 8-OH 5-HT2A [³H]DTBZ 5HT Uptake DPAT[¹²⁵I]DOI Ki (nM) ± IC₅₀ (nM) ± Ki(nM) ± Ki (nM) ± A₃ A₄ SEM SEM SEM SEMH CF₃ >10 μM  342 ± 103 — — CF₃ H >10 μM 1471 ± 65  — — H F >10 μM 200 ±51 — — F H >10 μM 133 ± 20 — —

Example 15 Synthesis of 2H-Oxazolo[2,3-b]quinazolin-5(3H)-one (Compound1a)

A dry 250 mL round bottom flask was charged with3-(2-chloroethyl)-2,4-quinazolinedione (2.00 g, 8.90 mmol), KI (148 mg,0.89 mmol), K₂CO₃ (2.46 g, 17.8 mmol), and dry acetonitrile (32 mL),then heated to 80° C. for 5 h. The mixture was concentrated, thenpartitioned between CH₂Cl₂ (75 mL) and H₂O (20 mL), and the layers wereseparated. The aqueous layer was further extracted with CH₂Cl₂ (25 mL),and the combined organic layers were dried (MgSO₄), filtered, andconcentrated to give compound 1a (1.66 g, 99%) as a white solid: 1H NMR(300 MHz, CDCl₃)δ 8.18 (dd, J=1.7, 8.0 Hz, 1H), 7.67 (ddd, J=1.7, 7.2,8.3 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.33 (ddd, J=1.1, 7.2, 8.3 Hz, 1H),4.76 (dd, J=7.7, 8.6 Hz, 2H), 4.37 (t, J=8.0, 8.6 Hz, 2H).

Example 16 Synthesis of2H-Oxazolo[3,2-a]thieno[2,3-d]pyrimidin-5(3H)-one (Compound 1b)

The compound was prepared as a light yellow solid according to SugiyamaM et al, Chem Pharm Bull 37, 2091-2102 (1989); incorporated by referenceherein.

Example 17 Synthesis of7,9-dibromo-2H-oxazolo[2,3-b]quinazolin-5(3H)-one (Compound 1c) and7-bromo-2H-oxazolo[2,3-b]quinazolin-5(3H)-one (Compound 1d).

To a stirred solution of 3-(2-Chloroethyl)-2,4(1H,3H)-quinazolinedione(2.5 g, 11.1 mmol) in CHCl₃ (50 mL) at room temperature, was addedBromine (1.14 mL, 22.2 mmol). The resulting solution was heated at 65°C. for 2 days at which time another 2 equivalents of bromine was added.Heating continued for 2 more days and another 2 equivalents of brominewas added. After 3 more days of heating, 4 equivalents of bromine wereadded to the solution and heating continued for 3 days. The solution wasthen cooled to room temperature, basified with sat. Na₂CO₃ and extractedwith CHCl₃ (5×50 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated affording compound 1. The crude product wascarried on without any further purification.

The crude reaction mixture from above was dissolved in CH₃CN (15 ml) andK₂CO₃ (1.37 g, 9.9 mmol) and KI (82 mg, 0.5 mmol) was added. Thereaction mixture was heated to 80° C. overnight. The mixture was thenconcentrated, partitioned between CH₂Cl₂ (75 mL) and H₂O (20 mL), andthe layers were separated. The aqueous layer was further extracted withCH₂Cl₂ (25 mL), and the combined organic layers were dried (Na₂SO₄),filtered, and concentrated to give the crude mixture. The compounds wereseparated on silica gel eluting with 10-25% EtOAc/CH₂Cl₂.

7,9-dibromo-2H-oxazolo[2,3-b]quinazolin-5(3H)-one (1c). The titlecompound was isolated in 19% yield (327 mg) as an off-white solid.R_(f)=0.4 (20% EtOAc/CH₂Cl₂). ¹H NMR (300 MHz, DMSO-d₆) δ 8.24 (d,J=2.48 Hz, 1H), 8.07 (d, J=2.20 Hz, 1H), 4.75 (t, J=8.26 Hz, 2H), 4.24(t, J=8.26 Hz, 2H).

7-bromo-2H-oxazolo[2,3-b]quinazolin-5(3H)-one (1d). The title compoundwas isolated in 29% yield (385 mg) as an off-white solid. R_(f)=0.2 (20%EtOAc/CH₂Cl₂). ¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (d, J=2.75 Hz, 1H), 7.85(dd, J=2.48, 8.53 Hz, 1H), 7.39 (d, J=8.53 Hz, 1H), 4.70 (t, J=7.98, Hz,2H), 4.23 (t, J=8.26 Hz, 2H).

Example 18 Synthesis of Ethyl1-benzyl-4-(trifluoromethylsulfonyloxy)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 2)

To a suspension of ethyl 1-benzyl-4-oxo-3-piperidinecarboxylatehydrochloride (3.32 g, 11.1 mmol) in H₂O (30 mL) was added potassiumcarbonate (2.76 g, 20.0 mmol), and the mixture was extracted with CH₂Cl₂(3×40 mL). The combined organic layers were dried (Na₂SO₄), filtered,and concentrated to give the free base (100%) as an oil which was usedwithout further purification. This keto-ester was dissolved in anhydrousDMF (20 mL), fitted with a septum, nitrogen inlet and cooled to 0° C.NaH (60% in mineral oil, 668 mg, 16.7 mmol) was added in one portion,and the solution was stirred at 0° C. for 10 min.N-phenyl-bis(trifluoromethanesulfonimide) (4.36 g, 12.2 mmol) was addedin one portion, and the solution was stirred at 0° C. for 1.5 h. Water(50 mL) was then added and the resulting mixture was extracted withEtOAc (3×50 mL). The combined organic layers were washed with H₂O (20mL), dried (Na₂SO₄), filtered, and concentrated. The residue waspurified by flash chromatography eluting with 0-15% EtOAc/hexanes togive Compound 2 (3.60 g, 83%) as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ7.34-7.25 (comp, 5H), 4.27 (q, J=7.2 Hz, 2H), 3.67 (s, 2H), 3.42 (t,J=2.7 Hz, 2H), 2.71 (t, J=5.4 Hz, 2H), 2.53-2.49 (m, 2H), 1.31 (t, J=7.2Hz, 3H).

Example 19 Synthesis of Ethyl1-benzyl-4-(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3d)

A 250 mL round bottom flask was charged with triflate 2 (2.71 g, 6.9mmol), 4-fluorophenyl boronic acid (2.11 g, 15.1 mmol), PdCl₂(PPh₃)₂(147 mg, 0.21 mmol), LiCl (875 mg, 20.6 mmol), and K₂CO₃ (5.71 g, 41.3mmol). The flask was evacuated and back-flushed with argon three times,anhydrous dioxane (100 mL) was added, and the flask was heated to 95° C.overnight. The flask was cooled to room temperature and CHCl₃ (500 mL)was added. The mixture was then washed with water (2×150 mL), brine (150mL), dried (MgSO₄), and concentrated. The residue was purified by flashchromatography eluting with 0-30% EtOAc/hexanes to give 3d (1.98 g,85%): R_(f)=0.34 (20% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ7.20-7.48 (m, 5H), 7.10 (dd, J=5.5, 8.8 Hz, 2H), 6.99 (t, J=8.8 Hz, 2H),3.91 (q, J=7.2 Hz, 2H), 3.70 (s, 2H), 3.31-3.49 (m, 2H), 2.61-2.72 (m,2H), 2.42-2.56 (m, 2H), 0.91 (t, J=7.2 Hz, 3H).

Example 20 Synthesis of Ethyl1-benzyl-4-(3-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(3e)

A 100 mL round bottom flask was charged with triflate 2 (800 mg, 2.0mmol), 3-fluorophenyl boronic acid (312 mg, 2.2 mmol), LiCl (258 mg, 6.1mmol), Na₂CO₃ (645 mg, 6.1 mmol). Pd(PPh₃)₄ (71.0 mg, 0.061 mmol). Theflask was evacuated and back-flushed with argon three times; toluene (10mL), EtOH (10 mL) and water (3 mL) were then added. The resultantmixture was heated to 85° C. for 20 h. The flask was cooled to roomtemperature, and EtOAc (40 mL) and water (15 mL) were added. The organiclayer was separated and, the aqueous layer was extracted with EtOAc (15mL). The combined organic layers were dried (Na₂SO₄) and concentrated.The residue was purified by flash chromatography eluting with 15-25%EtOAc/hexanes to give 3e (490 mg, 71%) as a light yellow oil: R_(f)=0.55(25% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.22 (comp, 6H),6.83-6.95 (comp, 3H), 3.90 (q, J=7.2 Hz, 2H), 3.69 (s, 2H), 3.37 (t,J=2.7 Hz, 2H), 2.66 (t, J=5.4 Hz, 2H), 2.49 (m, 2H) 0.89 (t, J=7.2 Hz,3H).

Example 21 Synthesis of Ethyl1-benzyl-4-phenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (Compound 3a)

Compound 3a was prepared from 2 and phenylboronic acid in 67% yieldusing the method of Example 19 or Example 20, described above. ¹H NMR(300 MHz, CDCl₃) δ 7.39-7.22 (comp, 8H), 7.18-7.13 (m, 2H), 3.86 (q,J=7.2 Hz, 2H), 3.70 (s, 2H), 3.39 (t, J=2.7 Hz, 2H), 2.65 (t, J=5.4 Hz,2H), 2.56-2.50 (m, 2H), 0.84 (t, J=7.2 Hz, 3H).

Example 22 Synthesis of Ethyl1-benzyl-4-(p-tolyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (3b)

Compound 3b was prepared from 2 and 4-methylphenylboronic acid in 81%yield using the method of Example 19 or Example 20, described above. ¹HNMR (300 MHz, CDCl₃) δ 7.40-7.25 (comp, 5H), 7.11 (d, J=7.5 Hz, 2H),7.03 (d, J=7.5 Hz, 2H), 3.90 (q, J=7.2 Hz, 2H), 3.68 (s, 2H), 3.38 (t,J=3.0 Hz, 2H), 2.64 (t, J=2.4 Hz, 2H), 2.55-2.47 (m, 2H), 2.33 (s, 3H),0.89 (t, J=7.2 Hz, 3H).

Example 23 Synthesis of Ethyl1-benzyl-4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3c)

Compound 3c was prepared from 2 and(2,3-dihydrobenzo[b][1,4]dioxin-5-yl) boronic acid in 81% yield usingthe method of Example 19 or Example 20, described above. ¹H NMR (300MHz, CDCl₃) δ 7.39-7.22 (comp, 5H), 6.78 (d, J=8.1 Hz, 1H), 6.68 (d,J=2.1 Hz, 1H), 6.63 (dd, J=1.8, 8.1 Hz, 1H), 4.24 (s, 4H), 3.94 (q,J=6.9 Hz, 2H), 3.67 (s, 2H), 3.36 (t, J=2.4 Hz, 2H), 2.62 (t, J=2.1 Hz,2H), 2.50-2.45 (m, 2H), 0.96 (t, J=6.9 Hz, 3H).

Example 24 Synthesis of Ethyl1-benzyl-4-(4-(trifluoromethyl)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3f)

Compound 3f was prepared from 2 and 4-trifluoromethylphenyl boronic acidin 82% yield using the method of Example 19 or Example 20, describedabove. ¹H NMR (300 MHz, CDCl₃) δ 7.57 (d, J=8.1 Hz, 2H), 7.39-7.27(comp, 5H), 7.23 (d, J=8.1 Hz, 2H), 3.87 (q, J=7.2 Hz, 2H), 3.70 (s,2H), 3.40 (t, J=2.7 Hz, 2H), 2.66 (t, J=5.4 Hz, 2H), 2.52-2.47 (m, 2H),0.84 (t, J=7.2 Hz, 3H).

Example 25 Synthesis of Ethyl1-benzyl-4-(3-(trifluoromethyl)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3g)

Compound 3g was prepared from 2 and 3-trifluoromethylphenyl boronic acidin 74% yield using the method of Example 19 or Example 20, describedabove. ¹H NMR (300 MHz, CDCl₃) δ 7.55-7.24 (comp, 9H), 3.86 (q, J=7.2Hz, 2H), 3.69 (s, 2H), 3.39 (t, J=2.7 Hz, 2H), 2.66 (t, J=5.4 Hz, 2H),2.54-2.48 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).

Example 26 Synthesis of Ethyl1-benzyl-4-(4-(dimethylamino)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3h)

Compound 3h was prepared from 2 and 4-N,N-dimethylaminolphenyl boronicacid in 67% yield using the method of Example 19 or Example 20,described above. ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.28 (comp, 5H), 7.05(d, J=9.0 Hz, 2H), 6.64 (d, J=9.0 Hz, 2H), 3.96 (q, J=7.2 Hz, 2H), 3.67(s, 2H), 3.38 (t, J=2.4 Hz, 2H), 2.94 (s, 6H), 2.63 (t, J=5.1 Hz, 2H),2.55-2.48 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

Example 27 Synthesis of Ethyl1-benzyl-4-(4-carbamoylphenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3i)

Compound 3i was prepared from 2 and 4-aminocarbonylphenyl boronic acidas a light yellow solid (134 mg, 82%) using the method of Example 19 orExample 20, described above. mp=184.0-186.0° C.; ¹H NMR (300 MHz, CDCl₃)δ 7.76 (d, J=7.8 Hz, 2H), 7.39-7.30 (comp, 5H), 7.23 (d, J=7.8 Hz, 2H),3.89 (q, J=7.2 Hz, 2H), 3.69 (s, 2H), 3.39 (t, J=2.7 Hz, 2H), 2.66 (t,J=5.4 Hz, 2H), 2.52-2.49 (m, 2H), 0.88 (t, J=7.2 Hz, 3H).

Example 28 Synthesis of Ethyl4-([1,1′-biphenyl]-4-yl)-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3j)

Compound 3j was prepared from 2 and 4-N,N-dimethylaminolphenyl boronicacid in 80% yield using the method of Example 19 or Example 20,described above: ¹H NMR (300 MHz, CDCl₃) δ 7.61-7.19 (comp, 14H), 3.91(q, J=7.2 Hz, 2H), 3.70 (s, 2H), 3.41 (t, J=2.7 Hz, 2H), 2.68 (t, J=5.1Hz, 2H), 2.60-2.52 (m, 2H), 0.87 (t, J=7.2 Hz, 3H).

Example 29 Synthesis of Ethyl1-benzyl-4-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3k)

Compound 3k was prepared from 2 and N-Boc-2-pyrroleboronic acid as ayellow oil (300 mg, 67%) using the method of Example 19 or Example 20,described above: R_(f)=0.43 (15% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃)δ 7.38-7.27 (comp, 5H), 7.26-7.22 (m, 1H), 6.12 (t, J=3.3 Hz, 1H), 5.92(dd, J=2.1, 3.3 Hz, 1H), 3.89 (q, J=7.2 Hz, 2H), 7.65 (br. s, 2H), 3.48(br. s, 1H), 3.25 (br. s, 1H), 2.61 (br. s, 2H), 2.47 (br. s, 2H), 1.53(s, 9H), 0.96 (t, J=7.2 Hz, 3H).

Example 30 Synthesis of Ethyl1-benzyl-4-(4-(ethoxycarbonyl)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3l)

Compound 3l was prepared from 2 and 4-ethoxycarbonyllphenylboronic acidin 50% yield using the method of Example 19 or Example 20, describedabove: ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, J=8.4 Hz, 2H), 7.39-7.25(comp, 5H), 7.21 (d, J=8.4 Hz, 2H), 4.36 (q, J=7.2 Hz, 2H), 3.87 (q,J=7.2 Hz, 2H), 3.69 (s, 2H), 3.39 (t, J=2.7 Hz, 2H), 2.66 (t, J=5.4 Hz,2H), 2.53-2.45 (m, 2H), 1.38 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H).

Example 31 Synthesis of Ethyl1-benzyl-4-(thiophen-2-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate (3m)

Compound 3m was prepared from 2 and 2-thienylboronic acid as a yellowoil (123 mg, 88%) using the method of Example 19 or Example 20,described above: R_(f)=0.33 (25% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃)δ 7.38-7.27 (comp, 5H), 7.26-7.24 (M, 1H), 6.97-6.93 (comp, 2H), 4.03(q, J=7.2 Hz, 2H), 3.66 (s, 2H), 3.36 (t, J=2.7 Hz, 2H), 2.67 (t, J=5.4Hz, 2H), 2.60-2.54 (m, 2H), 1.05 (t, J=7.2 Hz, 3H).

Example 32 Synthesis of Ethyl1-benzyl-4-(5-methylthiophen-2-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3n)

Compound 3n was prepared from 2 and 5-methyl-2-thienylboronic acid as ayellow oil (1.07 g, 86%) using the method of Example 19 or Example 20,described above: ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.25 (comp, 5H), 6.73(d, J=3.6 Hz, 1H), 6.60 (m, 1H), 4.07 (q, J=7.2 Hz, 2H), 3.65 (s, 2H),3.34 (t, J=2.7 Hz, 2H), 2.64 (t, J=5.1 Hz, 2H), 2.45 (s, 3H), 1.10 (t,J=7.2 Hz, 3H).

Example 33 Synthesis of Ethyl4-(4-acetylphenyl)-1-benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3p)

Compound 3p was prepared from 2 and 4-acetylphenylboronic acid in 77%yield using the method of Example 19 or Example 20, described above: ¹HNMR (300 MHz, CDCl₃) δ 7.91 (d, J=6.6 Hz, 2H), 7.40-7.25 (comp, 5H),7.24 (d, J=6.6 Hz, 2H), 3.89 (q, J=7.2 Hz, 2H), 3.69 (s, 2H), 3.39 (t,J=2.4 Hz, 2H), 2.66 (t, J=5.7 Hz, 2H), 2.59 (s, 3H), 2.53-2.47 (m, 2H),0.88 (t, J=7.2 Hz, 3H).

Example 34 Synthesis of Ethyl1-benzyl-4-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3q)

Compound 3q was prepared from 2 and 3-methoxyphenylboronic acid as ayellow oil (1.10 g, 95%) using the method of Example 19 or Example 20,described above. R_(f)=0.18 (15% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃)δ 7.39-7.27 (m, 5H), 7.21 (t, J=7.8 Hz, 1H), 6.79 (m, 1H), 6.74-6.68 (m,2H), 3.90 (q, J=7.2 Hz, 2H), 3.78 (s, 3H), 3.69 (2, 2 H), 3.38 (t, J=2.7Hz, 2H), 2.54-2.50 (m, 2H), 0.87 (t, J=7.2 Hz, 3H).

Example 35 Synthesis of Ethyl1-benzyl-4-(4-methoxyphenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3r)

Compound 3r was prepared from 2 and 4-methoxyphenylboronic acid as ayellow oil (497 mg, 92%) using the method of Example 19 or Example 20,described above. R_(f)=0.18 (15% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃)δ 7.38-7.25 (m, 5H), 7.09 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H),3.94 (q, J=7.8 Hz, 2H), 3.80 (s, 3H), 3.67 (s, 2H), 3.36 (t, J=2.4 Hz,2H), 2.64 (t, J=5.4 Hz, 2H), 2.53-2.49 (m, 2H), 0.92 (t, J=7.8 Hz, 3H).

Example 36 Synthesis of Ethyl1-benzyl-4-(4-((tert-butoxycarbonyl)amino)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3s)

Compound 3s was prepared from 2 and 3-(N-Boc-amino)phenylboronic acid asa light yellow solid (720 mg, 94%) using the method of Example 19 orExample 20, described above. mp=150.0-151.1° C.; R_(f)=0.10 (15%EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.26 (m, 7H), 7.08 (d,J=8.7 Hz, 2H), 6.45 (br. s, 1H), 3.90 (q, J=7.2 Hz, 2H), 3.67 (s, 2H),3.37 (t, J=2.4 Hz, 2H), 2.63 (t, J=5.4 Hz, 2H), 2.51-2.47 (m, 2H), 1.47(s, 9H), 0.92 (t, J=7.2 Hz, 3H).

Example 37 Synthesis of Ethyl1-benzyl-4-(4-ethylphenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3t)

Compound 3t was prepared from 2 and 4-ethylphenylboronic acid as a lightyellow oil (445 mg, 94%) using the method of Example 19 or Example 20,described above. R_(f)=0.20 (15% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃)δ 7.39-7.26 (m, 5H), 7.13 (d, J=7.8 Hz, 2H), 7.05 (d, J=7.8 Hz, 2H),3.88 (q, J=7.2 Hz, 2H), 3.69 (s, 2H), 3.38 (t, J=2.4 Hz, 2H), 2.67-2.60(m, 4H), 2.54-2.49 (m, 2H), 1.23 (t, J=7.5 Hz, 3H), 0.85 (t, J=7.2 Hz,3H).

Example 38 Synthesis of Ethyl1-benzyl-4-(4-isopropylphenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3u)

Compound 3u was prepared from 2 and 4-isopropylphenylboronic acid as alight yellow oil (344 mg, 94%) using the method of Example 19 or Example20, described above; R_(f)=0.25 (15% EtOAc/hexanes); ¹H NMR (300 MHz,CDCl₃) δ 7.40-7.26 (m, 5H), 7.15 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.4 Hz,2H), 3.84 (q, J=7.2 Hz, 2H), 3.69 (s, 2H), 3.38 (t, J=2.4 Hz, 2H), 2.87(hep, J=6.9 Hz, 1H), 2.65 (t, J=5.7 Hz, 2H), 2.53-2.49 (m, 2H), 1.23 (d,J=6.9 Hz, 6H), 0.80 (t, J=7.2 Hz, 3H).

Example 39 Synthesis of (E)-Ethyl1-benzyl-4-styryl-1,2,5,6-tetrahydropyridine-3-carboxylate (Compound 3v)

Compound 3v was prepared from 2 and trans-styrylboronic acid as a yellowoil (248 mg, 70%) using the method of Example 19 or Example 20,described above. R_(f)=0.20 (15% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃)δ 8.09 (d, J=16.2 Hz, 1H), 7.48-7.44, 2 H), 7.39-7.23 (m, 8H), 6.77 (d,J=16.2 Hz, 2H), 4.23 (q, J=7.2 Hz, 2H), 3.65 (s, 2H), 3.40 (s, 2H), 2.62(s, 2H), 1.32 (t, J=7.2 Hz, 3H).

Example 40 Synthesis of Ethyl1-benzyl-4-(2-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3x)

Compound 3x was prepared from 2 and 2-fluorophenylboronic acid as ayellow oil (570 mg, 91%) using the method of Example 19 or Example 20,described above. R_(f)=0.21 (15% EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃)δ 7.39-7.21 (m, 6H), 7.10-6.95 (3H), 3.90 (q, J=7.2 Hz, 2H), 3.70 (s,2H), 3.42 (t, J=3.0 Hz, 2H), 2.65 (t, J=5.4 Hz, 2H), 2.52-2.48 (m, 2H),0.87 (t, J=7.2 Hz, 3H).

Example 41 Synthesis of Ethyl1-benzyl-4-(m-tolyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (Compound3y)

Compound 3y was prepared using the method of Example 19 or Example 20,described above in 61% yield from 2 and m-tolyl boronic acid. ¹H NMR(300 MHz, CDCl₃) δ 7.43-7.26 (m, 5H), 7.20 (t, J=7.6 Hz, 1H), 7.08 (d,J=7.7 Hz, 1H), 6.99-6.91 (m, 2H), 3.90 (q, J=7.2 Hz, 2H), 3.69 (s, 2H),3.39 (t, J=2.5 Hz, 2H), 2.65 (t, J=5.5, Hz, 2H), 2.52 (dq, J=5.5, 2.8Hz, 2H), 2.33 (s, 3H), 0.86 (t, J=7.0 Hz, 3H).

Example 42 Synthesis of Ethyl1-benzyl-4-(o-tolyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (Compound3z)

Compound 3z was prepared using the method of Example 19 or Example 20,described above, in 91% yield from 2 and o-tolyl boronic acid. ¹H NMR(300 MHz, CDCl₃) δ 7.44-7.26 (comp., 5H), 7.19-7.07 (m, 3H), 7.00-6.88(m, 1H), 3.84 (qd, J=1.2, 7.1 Hz, 2H), 3.78-3.63 (m, 2H), 3.50 (d,J=16.5 Hz, 1H), 3.31 (d, J=16.8 Hz, 1H), 2.79-2.64 (m, 1H), 2.64-2.48(m, 1H), 2.40 (tt, J=2.86, 5.4 Hz, 2H), 2.19 (s, 3H), 0.80 (t, J=7.2 Hz,3H).

Example 43 Synthesis of Ethyl1-benzyl-4-(3-(dimethylamino)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3aa)

Compound 3aa was prepared using the method of Example 19 or Example 20,described above, in 99% yield from 2 and 3-(N,N-Dimethylamino)phenylboronic acid. ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.14 (comp., 6H), 6.67-6.62(m, 1H), 6.54-6.49 (m, 2H), 3.89 (q, J=7.2 Hz, 2H), 3.68 (s, 2H), 3.38(t, J=2.6 Hz, 2H), 2.91 (s, 6H), 2.68-2.61 (m, 2H), 2.54 (td, J=2.6, 5.2Hz, 2H), 0.87 (t, J=7.0 Hz, 3H).

Example 44 Synthesis of Ethyl1-benzyl-4-(2-(dimethylamino)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3bb)

Compound 3bb was prepared using the method of Example 19 or Example 20,described above, in 52% yield from 2 and2-(N,N-Dimethylamino)phenylboronic acid. ¹H NMR (300 MHz, CDCl₃) δ7.41-7.25 (comp., 5H), 7.16 (t, J=7.6 Hz, 1H), 6.64 (dd, J=7.4, 2.5 Hz,1H), 6.55-6.48 (m, 2H), 3.89 (qd, J=7.2, 1.1 Hz, 2H), 3.68 (s, 2H), 3.37(br. s., 2H), 2.91 (s, 5H), 2.65 (t, J=5.8 Hz, 2H), 2.53 (br. s., 2H),0.86 (td, J=7.2, 1.1 Hz, 3H).

Example 45 Synthesis of Ethyl1-benzyl-4-(3,4-dimethoxyphenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3dd)

Compound 3dd was prepared using the method of Example 19 or Example 20,described above in 93% yield from 2 and 3,4-Dimethoxyphenylboronic acid.¹H NMR (300 MHz, CDCl₃) δ 7.42-7.26 (comp., 5H), 6.87-6.78 (m, 1H),6.75-6.66 (m, 2H), 3.92 (q, J=7.2 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 4H),3.68 (s, 2H), 3.40-3.33 (m, 2H), 2.69-2.59 (m, 2H), 2.52 (dt, J=2.8, 5.4Hz, 2H), 0.92 (t, J=7.2 Hz, 3H).

Example 46 Synthesis of Ethyl1-benzyl-4-(3,4-bis(benzyloxy)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3ff)

Compound 3ff was prepared using the method of Example 19 or Example 20,described above in 87% yield from 2 and2-[3,4-bis(benzyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. ¹HNMR (300 MHz, CDCl3) δ 7.47-7.27 (comp., 15H), 6.87 (d, J=8.3 Hz, 1H),6.78 (d, J=2.2 Hz, 1H), 6.68 (dd, J=1.9, 8.3 Hz, 1H), 5.13 (d, J=12.1Hz, 4H), 3.81 (q, J=7.2 Hz, 2H), 3.67 (s, 2H), 3.38-3.29 (m, 2H),2.67-2.57 (m, 2H), 2.45 (dt, J=2.6, 5.6 Hz, 2H), 0.82 (t, J=7.2 Hz, 3H).

Example 47 Synthesis of Ethyl1-benzyl-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3gg)

Compound 3gg was prepared using the method of Example 19 or Example 20,described above in 99% yield from 2 and 1,4-Benzodioxane-6-boronic acid.¹H NMR (300 MHz, CDCl₃) δ 7.41-7.26 (comp., 5H), 6.79 (d, J=8.3 Hz, 1H),6.68 (d, J=2.2 Hz, 1H), 6.66-6.59 (m, 1H), 4.24 (s, 4H), 3.95 (q, J=7.2Hz, 2H), 3.67 (s, 2H), 3.36 (t, J=2.6 Hz, 2H), 2.68-6.58 (m, 2H),2.53-2.41 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).

Example 48 Synthesis of Ethyl1-benzyl-4-(2-(trifluoromethyl)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3hh)

Compound 3hh was prepared using the method of Example 19 or Example 20,described above in 80% yield from 2 and (2-Trifluoromethyl)phenylboronic acid. ¹H NMR (300 MHz, CDCl₃) δ 7.63 (d, J=8.0 Hz, 1H), 7.49 (d,J=7.71 Hz, 1H), 7.42-7.27 (m, 6H), 7.17 (d, J=7.7 Hz, 1H), 3.87-3.73 (m,3H), 3.68-3.50 (m, 2H), 3.27 (dd, J=2.8, 16.5 Hz, 1H), 2.54-2.38 (m,3H), 0.78 (t, J=7.0 Hz, 3H).

Example 49 Synthesis of Ethyl1-benzyl-4-(4-(trifluoromethoxy)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3ii)

Compound 3ii was prepared using the method of Example 19 or Example 20,described above in 86% yield from 2 and 4-Trifluoromethoxyphenylboronicacid. ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.26 (comp., 5H), 7.16 (s, 4H),3.88 (q, J=7.2 Hz, 2H), 3.69 (s, 2H), 3.38 (t, J=2.5 Hz, 2H), 2.65 (t,J=5.8 Hz, 2H), 2.53-2.46 (m, 2H), 0.84 (t, J=7.2 Hz, 3H).

Example 50 Synthesis of Ethyl1-benzyl-4-(3-(trifluoromethoxy)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3jj)

Compound 3jj was prepared using the method of Example 19 or Example 20,described above in 99% yield from 2 and 3-Trifluoromethoxyphenyl boronicacid. ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.26 (comp., 6H), 7.16-7.05 (comp.,2H), 7.02 (br. s., 1H), 3.87 (q, J=7.2 Hz, 2H), 3.69 (s, 2H), 3.39 (t,J=2.5 Hz, 2H), 2.65 (t, J=5.8 Hz, 2H), 2.50 (dq, J=5.5, 2.8 Hz, 2H),0.84 (t, J=7.2 Hz, 3H).

Example 51 Synthesis of Ethyl1-benzyl-1,2,5,6-tetrahydro-[4,4′-bipyridine]-3-carboxylate (Compound3kk)

Compound 3kk was prepared in 99% yield using the method of Example 19 orExample 20, described above from 2 and 4-Pyridinylboronic acid. ¹H NMR(300 MHz, CDCl₃) δ 8.57-8.51 (m, 2H), 7.40-7.27 (m, 5H), 7.09-7.03 (m,2H), 3.90 (q, J=7.2 Hz, 2H), 3.69 (s, 2H), 3.39 (t, J=2.7 Hz, 2H), 2.66(t, J=5.8 Hz, 2H), 2.47 (septet J=2.7 Hz, 2H), 0.88 (t, J=7.2 Hz, 3H).

Example 52 Synthesis of Ethyl1′-benzyl-1′,2′,5′,6′-tetrahydro-[3,4′-bipyridine]-3′-carboxylate(Compound 3ll)

Compound 3ll was prepared in 88% yield using the method of Example 19 orExample 20, described above from 2 and 3-Pyridinylboronic acid. ¹H NMR(300 MHz, CDCl₃) δ 8.51 (dd, J=1.6, 4.7 Hz, 1H), 8.39 (d, J=1.4 Hz, 1H),7.47 (dt, J=1.9, 7.8 Hz, 1H), 7.41-7.21 (m, 6H), 3.90 (q, J=7.2 Hz, 2H),3.70 (s, 2H), 3.41 (t, J=2.7 Hz, 2H), 2.66 (t, J=5.8 Hz, 2H), 2.56-2.44(m, 2H), 0.88 (t, J=7.2 Hz, 3H).

Example 53 Synthesis of Ethyl1-benzyl-4-(3,4-dichlorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3nn)

Compound 3nn was prepared using the method of Example 19 or Example 20,described above in 99% yield from 2 and 3,4-dichlorophenylboronic acid.¹H NMR (300 MHz, CDCl₃) δ 7.26-7.41 (m, 6H), 7.24 (d, J=1.9 Hz, 1H),6.98 (dd, J=8.3, 2.2 Hz, 1H), 3.94 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 3.37(t, J=2.8 Hz, 2H), 2.60-2.66 (m, 2H), 2.42-2.49 (m, 2H), 0.95 (t, J=7.0Hz, 3H).

Example 54 Synthesis of Ethyl1-benzyl-4-(3-((tert-butoxycarbonyl)amino)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate

(Compound 3qq)

Compound 3qq was prepared using the method of Example 19 or Example 20,described above in 96% yield from 2 and3-(N-Boc-amino)phenylboronicacid. ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.26 (m, 5H), 7.23-7.16 (m, 3H),6.81 (dt, J=2.55, 5.37 Hz, 1H), 6.42 (s, 1H), 4.11 (q, J=7.06 Hz, 0.5H),3.90 (q, J=7.15 Hz, 2H), 3.67 (s, 2H), 3.38-3.32 (m, 2H), 2.67-2.57 (m,2H), 2.50 (dq, J=2.83, 5.54 Hz, 2H), 1.50 (s, 9H), 1.25 (t, J=7.15 Hz,1H), 0.89 (t, J=7.15 Hz, 3H). (Exists as rotomers; seen especially inthe ester).

Example 55 Synthesis of Ethyl1-benzyl-4-(3,4-difluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3ss)

Compound 3ss was prepared using the method of Example 19 or Example 20,described above in 89% yield from 2 and 3,4-difluorophenylboronic acid.¹H NMR (300 MHz, CDCl₃) δ 7.43-7.25 (m, 5H), 7.09 (dt, J=8.36, 10.25 Hz,1H), 7.02-6.90 (m, 1H), 6.89-6.80 (m, 1H), 3.93 (q, J=7.15 Hz, 2H), 3.68(s, 2H), 3.36 (t, J=2.75 Hz, 2H), 2.64 (t, J=5.64 Hz, 2H), 2.46 (tt,J=2.75, 5.64 Hz, 2H), 0.95 (t, J=7.15 Hz, 3H).

Example 56 Synthesis of Ethyl1-benzyl-4-(3,4-difluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 3tt)

Compound 3tt was prepared using the method of Example 19 or Example 20,described above in 89% yield from 2 and 4-nitrophenylboronic acid. ¹HNMR (300 MHz, CDCl₃) δ 7.43-7.26 (m, 5H), 7.23 (d, J=7.43 Hz, 1H),7.14-6.96 (m, 3H), 3.90 (q, J=7.15 Hz, 2H), 3.70 (s, 2H), 3.42 (t,J=2.75 Hz, 2H), 2.71-2.59 (m, 2H), 2.55-2.43 (m, 2H), 0.88 (t, J=7.15Hz, 3H).

Example 57 Synthesis of1-benzyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (Compound 14)

Compound 14 was prepared from 13 and 4-fluorophenyl boronic acid as ayellow oil (1.00 g, 76%) using the method of Example 19 or Example 20,described above: R_(f)=0.48 (20% EtOAc/Hexanes); ¹H NMR (300 MHz, CDCl₃)δ 7.19-7.52 (m, 7H), 6.99 (t, J=8.8 Hz, 2H), 5.95-6.08 (m, 1H), 3.64 (s,2H), 3.16 (q, J=2.8 Hz, 2H), 2.71 (t, J=5.8 Hz, 2H), 2.44-2.61 (m, 2H).

Example 58 General Procedure Used in Reduction and Debenzylation ofCompounds

To a 50 mL round bottom flask was added 10% Pd/C (225 mg, 0.10 mmol, 50%wet) followed by the addition of a solution of 3 (350 mg, 1 mmol) inEtOH (10 mL). The flask was evacuated and back-flushed with H₂ threetimes, and the reaction mixture was stirred under a static atmosphere ofH₂ at room temperature (unless otherwise noted) for 24-72 hrs. Thesuspension was filtered through a pad of celite, washing with EtOH. Thecombined filtrate and washings were concentrated and purified by flashchromatography eluting with 0-10% MeOH/EtOAc (1% Et₃N) to give pure 4.

Example 59 Synthesis of (±) syn-ethyl 4-phenylpiperidine-3-carboxylate(Compound 4a)

Compound 4a was prepared from 3a in 73% yield using the method ofExample 58 above. ¹H NMR (300 MHz, CDCl₃) δ 7.31-7.17 (comb, 5H), 3.86(q, J=7.2 Hz, 2H), 3.37-3.27 (comp, 2H), 3.16-2.95 (comp, 2H), 2.78-2.68(comp, 2H), 2.36 (dq, J=4.5, 12.6 Hz, 1H), 1.67 (dd, J=3.0, 12.9 Hz,1H), 0.92 (t, J=7.2 Hz, 3H).

Example 60 Synthesis of (±) syn-ethyl4-(p-tolyl)piperidine-3-carboxylate (Compound 4b)

Compound 4b was prepared from 3b in 68% yield using the method ofExample 58 above. ¹H NMR (300 MHz, CDCl₃) δ 7.11-7.03 (comp, 4H), 3.87(q, J=7.2 Hz, 2H), 3.35-3.27 (comp, 2H), 3.02-2.91 (comp, 2H), 2.76-2.68(comp, 2H), 2.40-2.19 (comp, 4H), 1.67-1.58 (m, 1H), 0.94 (t, J=7.2 Hz,3H).

Example 61 Synthesis of (±) syn-ethyl4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperidine-3-carboxylate

Compound 4c was prepared from 3c in 25% yield using the method ofExample 58 above. ¹H NMR (300 MHz, CDCl₃) δ 6.77 (d, J=8.1 Hz, 1H), 6.69(d, J=2.1 Hz, 1H), 6.66 (dd, J=2.1, 7.8 Hz, 1H), 4.22 (s, 4H), 4.00-3.85(m, 2H), 3.33-3.26 (comp, 2H), 2.96-2.87 (comp, 2H), 2.74-2.65 (comp,2H), 2.25 (dq, J=4.2, 12.6 Hz, 1H), 1.61 (dd, J=3.0, 13.2 Hz, 1H), 1.00(t, J=7.2 Hz, 3H).

Example 62 Synthesis of (±) syn-ethyl4-(4-fluorophenyl)piperidine-3-carboxylate (Compound 4d)

Compound 4d was prepared from 3d as a yellow oil (751 mg, 58%) using themethod of Example 58 above. R_(f)=0.21 (10% MeOH/CH₂Cl₂); ¹H NMR (300MHz, CDCl₃) δ 7.14 (dd, J=5.5, 8.8 Hz, 2H), 6.96 (t, J=8.8 Hz, 2H), 3.87(q, J=7.2 Hz, 2H), 3.24-3.40 (m, 2H), 2.88-3.05 (m, 2H), 2.63-2.79 (m,2H), 2.30 (qd, J=4.4, 12.9 Hz, 1H), 1.64 (dq, J=2.8, 12.9 Hz, 1H), 0.94(t, J=7.2 Hz, 3H).

Example 63 Synthesis of (±) syn-ethyl4-(3-fluorophenyl)piperidine-3-carboxylate (Compound 4e)

Compound 4e was prepared from 3e as a yellow oil (247 mg, 67%) using themethod of Example 58 above. R_(f)=0.05 (10% MeOH/CH₂Cl₂); ¹H NMR (300MHz, CDCl₃) δ 7.28-7.21 (m, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.93-6.86 (m,2H), 3.89 (dq, J=1.8, 6.9 Hz, 2H), 3.38-3.28 (comp, 2H), 3.61-2.93(comp, 2H), 2.77-2.68 (comp, 2H), 2.30 (dq, J=4.5, 12.9 Hz, 1H), 1.67(dq, J=2.7, 13.2 Hz, 1H).

Example 64 Synthesis of (±) syn-ethyl4-(4-(trifluoromethyl)phenyl)piperidine-3-carboxylate (Compound 4f)

Compound 4f was prepared from 3f in 92% yield using the method ofExample 58 above. ¹H NMR (300 MHz, CDCl₃) δ 7.54 (d, J=7.8 Hz, 2H), 7.32(d, J=7.8 Hz, 2H), 3.87 (q, J=7.2 Hz, 2H), 3.40-3.30 (comp, 2H),3.22-3.04 (m, 1H), 2.98 (dd, J=3.9, 13.8 Hz, 1H), 2.79-2.70 (comp, 2H),2.36 (dq, J=4.2, 12.6 Hz, 1H), 1.84-1.75 (m, 1H), 0.92 (t, J=7.2 Hz,3H).

Example 65 Synthesis of (±) syn-ethyl4-(3-(trifluoromethyl)phenyl)piperidine-3-carboxylate (Compound 4g)

Compound 4g was prepared from 3g in 74% yield using the method ofExample 58 above. ¹H NMR (300 MHz, CDCl₃) δ 7.49-7.38 (comp, 4H), 3.86(q, J=6.9 Hz, 2H), 3.40-3.30 (comp, 2H), 3.08 (dt, J=3.6, 12.9 Hz, 1H),2.98 (dd, J=3.6, 13.8 Hz, 1H), 2.80-2.69 (comp, 2H), 2.34 (dq, J=3.9,12.9 Hz, 1H), 1.68 (dd, J=3.0, 13.2 Hz, 1H), 0.91 (t, J=6.9 Hz, 3H).

Example 66 Synthesis of (±) syn-ethyl4-(4-(dimethylamino)phenyl)piperidine-3-carboxylate (Compound 4h)

Compound 4h was prepared from 3h in 50% yield using the method ofExample 58 above. ¹H NMR (300 MHz, CDCl₃) δ 7.05 (d, J=8.7 Hz, 2H), 6.68(d, J=8.7 Hz, 2H), 3.90 (q, J=6.9 Hz, 2H), 3.33-3.29 (comp, 2H),2.96-2.82 (comp, 8H), 2.72-2.67 (comp, 2H), 2.30 (dq, J=4.2, 13.2 Hz,1H), 1.64 (dd, J=2.7, 13.2 Hz, 1H), 0.98 (t, J=6.9 Hz, 3H).

Example 67 Synthesis of (±) syn-ethyl4-(4-carbamoylphenyl)piperidine-3-carboxylate (Compound 4i)

Compound 4i was prepared from 3i as a white solid (193 mg, 68%) usingthe method of Example 58 above except stirring at 45° C.: R_(f)=0.10(10% MeOH/CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, J=8.1 Hz, 2H),7.23 (d, J=8.1 Hz, 2H), 6.05 (br. s, 1H), 5.53 (br. s, 1H), 3.91-3.75(m, 2H), 3.36-3.26 (comp, 2H), 3.07 (dt, J=4.2, 12.6 Hz, 1H), 2.95 (dd,J=3.9, 14.1 Hz, 1H), 2.81-2.67 (comp, 2H), 2.32 (dq, J=4.2, 12.9 Hz,1H), 1.70 (dd, J=2.7, 13.2 Hz, 1H), 0.89 (t, J=7.2 Hz, 3H).

Example 68 Synthesis of (±) syn-ethyl4-([1,1′-biphenyl]-4-yl)piperidine-3-carboxylate (Compound 4j)

Compound 4j was prepared from 3j in 70% yield using the method ofExample 58 above. ¹H NMR (300 MHz, CDCl₃) δ 7.59-7.50 (comp, 4H),7.54-7.39 (m, 2H), 7.36-7.24 (comp, 3H), 3.89 (q, J=7.2 Hz, 2H),3.39-3.31 (comp, 2H), 3.11-2.96 (comp, 2H), 2.82-2.71 (comp, 2H), 2.38(dq, J=3.9, 12.9 Hz, 1H), 2.25 (br. s, 1H), 1.74-1.67 (m, 1H), 0.92 (t,J=7.2 Hz, 3H).

Example 69 Synthesis of (±) syn-ethyl4-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)piperidine-3-carboxylate(Compound 4k)

Compound 4k was prepared from 3k as a colorless oil (166 mg, 38%) usingthe method of Example 58 above. R_(f)=0.25 (10% MeOH/CH₂Cl₂); ¹H NMR(300 MHz, CDCl₃) δ 7.19 (dd, J=1.8, 3.3 Hz, 1H), 6.04 (t, J=3.3 Hz, 1H),5.95-5.92 (m, 1H), 3.88-3.79 (m, 2H), 3.72 (dt, J=1.8, 12.9 Hz, 1H),3.30-3.22 (m, 2H), 3.06-3.02 (m, 1H), 2.91 (dd, J=3.6, 14.1 Hz, 1H),2.76-2.68 (m, 1H), 2.09 (dq, J=3.9, 12.6 Hz, 1H), 1.72-1.64 (m, 1H),1.58 (s, 9H), 0.98 (t, J=7.2 Hz, 3H).

Example 70 Synthesis of (±) syn-ethyl4-(4-(ethoxycarbonyl)phenyl)piperidine-3-carboxylate (Compound 4l)

Compound 4l was prepared from 3l in 51% yield using the method ofExample 58 above. ¹H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.7 Hz, 2H), 7.26(d, J=8.7 Hz, 2H), 3.35 (q, J=7.2 Hz, 2H), 3.95-3.79 (m, 2H), 3.39-3.29(comp, 2H), 3.11-2.95 (comp, 2H), 2.81-2.69 (comp, 2H), 2.36 (dq, J=3.9,12.6 Hz, 1H), 1.68 (dd, J=2.7, 13.2 Hz, 1H), 1.37 (t, J=7.2 Hz, 3H),0.94 (t, J=7.2 Hz, 3H).

Example 71 Synthesis of (±) syn-ethyl4-(thiophen-2-yl)piperidine-3-carboxylate (Compound 4m)

The olefin was reduced according to the method of Example 58 above andwas prepared from 3m as a yellow oil (342 mg, 45%). R_(f)=0.22 (25%EtOAc/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.24 (comp, 5H), 7.13(dd, J=1.5, 4.8 Hz, 1H), 6.93-6.87 (comp, 2H), 4.05-3.95 (m, 2H), 3.55(dd, J=13.5, 55.8 Hz, 2H), 3.36 (br. s, 1H), 3.02-2.97 (m, 2H), 2.84(br. s, 1H), 2.58-2.35 (comp, 3H), 2.04-1.97 (m, 1H), 1.07 (t, J=7.2 Hz,3H).

Debenzylation was performed according to the following procedure: Around bottom flask was charged with 4a (342 mg, 1.04 mmol), thenα-chloroethyl chloroformate (ACE-Cl, 1.05 mL, 14.1 mmol) was added undernitrogen by syringe in one portion, and the reaction mixture stirred for2.5 h at 100° C. Volatiles were removed in vacuo and the residue wastreated with anhydrous EtOH (20 mL). The flask was then heated to refluxfor 20 min and concentrated in vacuo. The solid residue was purified byflash chromatography using 0-10% MeOH/CH₂Cl₂ (1% Et₃N) to give 4m (219mg, 87%) as a yellow oil: R_(f)=0.18 (10% MeOH/CH₂Cl₂, 1% Et₃N); ¹H NMR(300 MHz, CDCl₃) δ 7.14 (dd, J=1.2, 5.1 Hz, 1H), 6.91 (dd, J=3.6, 5.1Hz, 1H), 6.82 (d, J=3.6 Hz, 1H), 3.96 (q, J=6.9 Hz, 2H), 3.39-3.21(comp, 3H), 2.97 (dd, J=3.9, 13.8 Hz, 1H), 2.85 (dd, J=3.6, 7.8 Hz, 1H),2.74 (ddd, J=3.3, 11.4, 16.8 Hz, 1H), 2.35-2.21 (m, 1H), 1.88-1.81 (m,1H), 1.04 (t, J=6.9 Hz, 3H).

Example 72 Synthesis of (±) syn-ethyl4-(5-methylthiophen-2-yl)piperidine-3-carboxylate (Compound 4n)

The olefin was reduced according to the method of Example 52 above andprepared as a colorless oil (501 mg, 47%). ¹H NMR (300 MHz, CDCl₃) δ7.33-7.22 (comp, 5H), 6.63 (d, J=3.6 Hz, 1H), 6.54-6.52 (m, 1H),4.07-3.95 (m, 2H), 3.53 (dd, J=13.5, 56.4 Hz, 2H), 3.29 (br. s, 1H),2.97-2.92 (m, 2H), 2.81 (br. s, 1H), 2.54 (br. s, 1H), 2.43-2.34 (comp,5H), 1.99-1.93 (m, 1H), 1.10 (t, J=7.2 Hz, 3H).

Compound 4n was prepared as a yellow oil (400 mg, 100%) using theprocedure described in Example 71 above. R_(f)=0.22 (10% MeOH/CH₂Cl₂);¹H NMR (300 MHz, CDCl₃) δ 6.60 (d, J=3.6 Hz, 1H), 6.55 (dd, J=1.2, 3.3Hz, 1H), 4.11-4.05 (m, 2H), 3.69 (dd, J=5.1, 10.5 Hz, 1H), 3.41 (d,J=6.0 Hz, 2H), 3.38-3.16 (comp, 3H), 2.42 (s, 3H), 2.32-2.19 (m, 2H),1.11 (t, J=7.2 Hz, 3H).

Example 73 Synthesis of (±) syn-ethyl4-(4-(1-hydroxyethyl)phenyl)piperidine-3-carboxylate (Compound 4p)

Compound 4p was prepared from 3p in 41% yield using the method ofExample 58 above. ¹H NMR (300 MHz, CDCl₃) δ 7.29 (d, J=8.1 Hz, 2H), 7.19(d, J=8.1 Hz, 2H), 4.87 (q, J=6.3 Hz, 1H), 3.88 (q, J=6.9 Hz, 2H),3.36-3.28 (comp, 2H), 3.16-2.93 (comp, 2H), 2.77-2.67 (comp, 2H), 2.34(dq, J=4.2, 12.9 Hz, 1H), 1.70-1.63 (m, 1H), 1.46 (d, J=6.3 Hz, 3H),0.93 (t, J=6.9 Hz, 3H).

Example 74 Synthesis of (±) syn-Ethyl4-(3-methoxyphenyl)piperidine-3-carboxylate (Compound 4q)

Compound 4q was prepared from 3q as a light yellow oil (839 mg, 100%)using the method of Example 58 above. ¹H NMR (300 MHz, CDCl₃) δ7.23-7.18 (m, 1H), 6.79-6.72 (m, 3H), 3.89 (q, J=7.2 Hz, 2H), 3.78 (s,3H), 3.48 (br. s, 1H), 3.39-3.33 (m, 2H), 3.07-2.98 (m, 2H), 2.84-2.75(m, 2H), 2.33 (dq, J=12.9, 4.2 Hz, 1H), 1.71 (dd, J=13.2, 2.4 Hz, 1H),0.94 (t, J=7.2 Hz, 3H).

Example 75 Synthesis of (±) syn-Ethyl4-(4-methoxyphenyl)piperidine-3-carboxylate (Compound 4r)

Compound 4r was prepared from 3r as a yellow waxy solid (361 mg, 96%)using the method of Example 58 above. R_(f)=0.07 (10% MeOH/CH₂Cl₂); ¹HNMR (300 MHz, CDCl₃) δ 7.10 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H),3.87 (q, J=7.2 Hz, 2H), 3.78 (s, 3H), 3.35-3.27 (m, 2H), 3.01-2.92 (m,2H), 2.77-2.66 (m, 2H), 2.30 (dq, J=12.9, 4.5 Hz, 1H), 1.63 (dd, J=13.2,2.4 Hz, 1H), 0.94 (t, J=7.2 Hz, 3H).

Example 76 Synthesis of (±) syn-Ethyl4-(3-((tert-butoxycarbonyl)amino)phenyl)piperidine-3-carboxylate(Compound 4s)

Compound 4s was prepared from 3s as an off-white solid (307 mg, 60%)using the method of Example 58 above. mp=154.5-156.5° C.; R_(f)=0.05(10% MeOH/CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃) δ 7.28-7.16 (m, 3H), 6.86 (m,1H), 6.45 (br. s, 1H), 3.90 (q, J=7.2 Hz, 2H), 3.35-3.27 (m, 2H),3.02-2.92 (m, 2H), 2.79-2.67 (m, 2H), 2.32 (dq, J=12.6, 4.5 Hz, 1H),1.92 (br. s, 1H), 1.63 (d, J=12.6 Hz, 1H), 1.51 (s, 9 H), 0.97 (t, J=7.2Hz, 3H).

Example 77 Synthesis of (±)-syn-Ethyl 4-(ethyl)piperidine-3-carboxylate(Compound 4t)

Compound 4t was prepared according to the method of Example 58 abovefrom 3t in 95% yield using 10% Pd/C at 1 atm of H₂ for 18 hours. ¹H NMR(300 MHz, CDCl₃) δ 7.19-7.00 (comp., 4H), 3.87 (qt, J=1.10, 6.88 Hz,2H), 3.41-3.26 (m, 2H), 3.07-2.92 (m, 2H), 2.82-2.69 (m, 2H), 2.61 (q,J=7.71 Hz, 2H), 2.52-2.41 (m, 1H), 2.40-2.23 (m, 1H), 1.72-1.62 (m, 1H),1.20 (t, J=7.57 Hz, 3H), 0.92 (t, J=7.15 Hz, 3H).

Example 78 Synthesis of (±)-syn-Ethyl4-(isopropyl)piperidine-3-carboxylate (Compound 4u)

Compound 4u was prepared according to the method of Example 58 abovefrom 3u in 95% yield using 10% Pd/C at 1 atm of H₂ for 18 hours. ¹H NMR(300 MHz, CDCl₃) δ 7.15 (d, J=8.26 Hz, 2H), 7.10 (d, J=8.53 Hz, 2H),3.98-3.75 (m, 2H), 3.40-3.21 (m, 2H), 3.06-2.67 (m, 5H), 2.32 (qd,J=4.27, 12.80 Hz, 1H), 1.70 (dq, J=2.20, 13.76 Hz, 1H), 1.22 (d, J=6.88Hz, 6H), 0.88 (t, J=7.15 Hz, 3H).

Example 79 Synthesis of (±)-syn-Ethyl4-phenethylpiperidine-3-carboxylate (Compound 4v)

Compound 4v was prepared according to the method of Example 58 above andisolated as a yellow oil from 3v in 39% yield using 10% Pd/C at 1 atm ofH₂ and 45° C. for 18 hours. ¹H NMR (300 MHz, CDCl₃) δ 7.33-7.26 (m, 2H),7.22-7.10 (m, 3H), 4.25-4.06 (m, 2H), 3.25 (dd, 4H), 3.14 (dt, J=3.61,13.42 Hz, 1H), 2.84 (dd, J=3.71, 13.62 Hz, 1H), 2.73-2.57 (m, 6H),1.91-1.70 (m, 1H), 1.70-1.50 (m, 4H), 1.27 (t, J=7.15 Hz, 3H).

Example 80 Synthesis of (±)-syn-Ethyl4-(3-fluorophenyl)piperidine-3-carboxylate (Compound 4x)

Compound 4x was isolated as a yellow oil in 42% yield from 3x accordingto method of Example 58 above. ¹H NMR (300 MHz, CDCl₃) δ 7.24-7.13 (m,2H), 7.10-6.95 (m, 2H), 3.85 (q, J=7.15 Hz, 2H), 3.42-3.27 (m, 3H), 2.99(dd, J=3.71, 13.90 Hz, 1H), 2.88 (t, J=4.27 Hz, 1H), 2.78 (ddd, J=2.89,12.18, 13.55 Hz, 1H), 2.34 (qd, J=4.27, 12.80 Hz, 1H), 1.59 (dq, J=3.11,12.97 Hz, 1H), 0.90 (t, J=7.15 Hz, 3H).

Example 81 Synthesis of (±)-syn-Ethyl4-(m-tolyl)piperidine-3-carboxylate (Compound 4y)

Compound 4y was prepared according to the method of Example 58 from 3yin 95% yield using 10% Pd/C at 1 atm of H₂ for 18 hours. ¹H NMR (300MHz, CDCl₃) δ 7.16 (t, J=8.0, 1 H), 7.03-6.92 (m, 3H), 4.93 (br. s.,1H), 3.88 (q, J=7.0 Hz, 2H), 3.44-3.31 (m, 2H), 3.13-3.01m, 2H),2.91-2.79 (m, 2H), 2.43-2.31 (m, 1H), 2.30 (s, 3H), 1.83-1.70 (m, 1H),0.92 (t, J=7.2 Hz, 3H).

Example 82 Synthesis of (±)-syn-Ethyl4-(o-tolyl)piperidine-3-carboxylate (Compound 4z)

Compound 4z was prepared according to the method of Example 58 from 3zin 37% yield using Pt₂O at 3 atm of H₂ for 5 days. ¹H NMR (300 MHz,CDCl₃) δ 7.22-7.09 (m, 3H), 7.04-6.98 (m, 1H), 4.01-3.83 (m, 2H),3.78-3.65 (m, 2H), 3.54-3.42 (m, 2H), 3.28 (td, J=12.3, 3.2 Hz, 1H),3.14 (q, J=3.8 Hz, 1H), 2.58 (tq, J=3.9, 2.8 Hz, 1H), 2.37 (s, 3H), 2.02(dd, J=14.4, 3.2 Hz, 1H), 0.89 (t, J=7.2 Hz, 3H).

Example 83 Synthesis of (±)-syn-Ethyl4-(3-(dimethylamino)phenyl)piperidine-3-carboxylate (Compound 4aa)

Compound 4aa was prepared according to the method of Example 58 abovefrom 3aa in 33% yield using Pt₂O at 1 atm of H₂ for 4 days. ¹H NMR (300MHz, CDCl₃) δ 7.15 (t, J=8.1 Hz, 1H), 6.66-6.58 (m, 1H), 6.52-6.44 (m,2H), 3.99 (m, 2H), 3.62 (dt, J=4.4, 3.6 Hz, 2H), 3.44 (dd, J=13.5, 3.3Hz, 1H), 3.35 (s, 6H), 2.40-2.57 (m, 1H), 2.08-2.21 (m, 1H), 0.98 (t,J=7.2 Hz, 3H).

Example 84 Synthesis of (±)-syn-Ethyl4-(2-(dimethylamino)phenyl)piperidine-3-carboxylate (Compound 4bb)

Compound 4bb was prepared according to the method of Example 58 abovefrom 3bb in 78% yield using 10% Pd/C at 3 atm of H₂ for 2 days. ¹H NMR(300 MHz, CDCl₃) δ 7.25-7.11 (m, 2H), 7.11-6.90 (m, 2H), 3.96-3.75 (m,2H), 3.75-3.62 (m, 2H), 3.58 (d, J=13.2 Hz, 1H), 3.44-3.21 (m, 2H), 3.13(td, J=12.7, 2.8 Hz, 1H), 2.61 (s, 6H), 2.46 (dd, J=13.5, 3.3 Hz, 1H),1.84 (dd, J=14.2, 2.9 Hz, 1H), 0.82 (t, J=7.2 Hz, 3H).

Example 85 Synthesis of Ethyl4-(3,4-dichlorophenyl)piperidine-3-carboxylate (Compound 4cc)

A dry 50-mL round bottom flask was charged with SM (200 mg, 0.49 mmol)and dry THF (5 mL). The solution was cooled to −78° C. MeOH (1 mL) wasthen added to the chilled solution immediately followed by SmI2 (19.6mL, 1.97 mmol, 0.1 M in THF). The reaction mixture turned blue and wasstirred for 1.5 hours. The mixture was quenched by the addition of water(10 mL) and warmed to room temperature at which time the reactionmixture turned yellow. The mixture was diluted with EtOAc and washedwith saturated NaHCO₃ solution. The aqueous layer was further extractedwith EtOAc. The combined extracts were then washed with brine, driedover Na₂SO₄, concentrated and purified via silica gel chromatography(10-100% EtOAc/Hexanes). The reduced intermediate was obtained as a paleyellow oil (140 mg) in 70% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.38(dd, J=14.6, 8.3 Hz, 1H), 7.29-7.21 (m, 1H), 7.05-6.92 (m, 1H),6.68-6.51 (m, 1H),4.42-4.25 (m, 1H), 3.96 (dq, J=18.1, 7.2 Hz, 2H), 3.70(t, J=5.8 Hz, 3H), 2.93 (td, J=11.9, 4.0 Hz, 1H), 2.49 (br. s., 1H),1.89-1.78 (m, 3H), 1.08-0.93 (m, 3H).

The product (a mixture of diasteromers) was dissolved in methanol (1 mL)and stirred overnight. The solvent was then removed under reducedpressure to afford the pure title compound in quantitative yield. ¹H NMR(300 MHz, CDCl₃) δ ppm 7.47-7.35 (m, 2H), 7.33 (d, J=1.9 Hz, 1H), 7.12(dd, J=8.5, 2.2 Hz, 1H), 7.04 (dd, J=8.3, 2.2 Hz, 1H), 4.02 (q, J=7.2Hz, 2H), 3.92 (qd, J=7.1, 1.8 Hz, 1H),3.83-3.56 (m, 3H), 3.51-3.12 (m,4H),3.10-2.89 (m, 2H), 2.58-2.24 (m, 1H), 2.19-1.92 (m, 1H), 0.99 (q,J=7.2 Hz, 6H).

Example 86 Synthesis of (±)-syn-ethyl4-(3,4-dimethoxyphenyl)piperidine-3-carboxylate (Compound 4dd)

Compound 4dd was prepared according to the method of Example 58 abovefrom 3dd in 30% yield using 10% Pd/C at 1 atm of H₂ for 5 days. ¹H NMR(300 MHz, CDCl₃) δ 6.84-6.77 (m, 1H), 6.72-6.64 (m, 2H), 4.07-3.90 (m,2H), 3.85 (s, 6H), 3.70-3.57 (m, 2H), 3.45 (dd, J=13.5, 3.6 Hz, 1H),3.35-3.12 (m, 2H), 2.61-2.38 (m, 1H), 2.20-2.05 (m, 1H), 0.98 (t, J=7.2Hz, 3H).

Example 87 Synthesis of (±)-syn-Ethyl4-(3,4-dihydroxyphenyl)piperidine-3-carboxylate (Compound 4ff)

Compound 4ff was prepared according to the method of Example 58 abovefrom 3ff in 86% yield using 10% Pd/C at 1 atm of H₂ for 20 hrs. ¹H NMR(300 MHz, MeOD) δ 6.67 (d, J=8.3 Hz, 1H), 6.63 (d, J=2.2 Hz, 1H), 6.51(dd, J=7.8, 2.1 Hz, 1H), 3.98-3.81 (m, 2H), 3.24 (s, 1H), 3.07-2.89 (m,2H), 2.84-2.65 (m, 2H), 2.28 (dd, J=13.1, 4.0 Hz, 1H), 1.67 (dd, J=13.5,3.0 Hz, 1H), 0.96 (t, J=7.2 Hz, 3H).

Example 88 Synthesis of (±)-syn-Ethyl4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)piperidine-3-carboxylate(Compound 4gg)

Compound 4gg was prepared according to the method of Example 58 abovefrom 3gg using 10% Pd/C at 1 atm of H₂ for 20 hrs. ¹H NMR (300 MHz,CDCl₃) δ 6.79 (d, J=8.3 Hz, 1H), 6.67-6.59 (m, 2H), 4.23 (s, 4H), 4.02(q, J=6.9 Hz, 2H), 3.67-3.54 (m, 2H), 3.41 (dd, J=13.5, 3.6 Hz, 1H),3.29-3.19 (m, 2H), 3.19-3.10 (m, 1H), 2.49-2.31-2.49 (m, 1H), 2.17-2.02(m, 1H), 1.01 (t, J=7.2 Hz, 3H).

Example 89 Synthesis of (±)-syn-Ethyl4-(2-(trifluoromethyl)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 4hh)

Compound 4hh was prepared according to the method of Example 58 abovefrom 3hh using 10% Pd/C at 1 atm of H₂ for 24 hrs. ¹H NMR (300 MHz,CDCl₃) δ 7.66 (d, J=7.2 Hz, 1H), 7.55 (t, J=7.3 Hz, 1H), 7.44 (t, J=7.7Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 4.13 (d, J=17.6 Hz, 1H), 3.88 (q, J=7.2Hz, 3H), 3.64-3.52 (m, 1H), 3.17 (ddd, J=12.5, 10.5, 4.8 Hz, 1H), 2.60(d, J=18.4 Hz, 1H), 0.82 (t, J=7.2 Hz, 3H).

Example 90 Synthesis of (±)-syn-Ethyl4-(4-(trifluoromethoxy)phenyl)piperidine-3-carboxylate (Compound 4ii)

Compound 4ii was prepared according to the method of Example 58 abovefrom 3ii in 97% yield using 10% Pd/C at 1 atm of H₂ for 24 hours. ¹H NMR(300 MHz, CDCl3) δ 7.25-7.09 (m, 5H), 6.18 (br. s., 1H), 3.90 (q, J=7.2Hz, 2H), 3.57-3.41 (m, 2H), 3.28-3.14 (m, 2H), 2.89-3.04 (m, 2H), 2.39(m, 1H), 1.89 (dd, J=13.8, 3.0 Hz, 1H), 0.91 (t, J=7.2 Hz, 3H).

Example 91 Synthesis of (±)-syn-Ethyl4-(3-(trifluoromethoxy)phenyl)piperidine-3-carboxylate (Compound 4jj)

Compound 4jj was prepared according to the method of Example 58 abovefrom 3jj in 74% yield using 10% Pd/C at 1 atm of H₂ for 24 hrs. ¹H NMR(300 MHz, CDCl₃) δ 7.31 (t, J=7.7 Hz, 1H), 7.17-7.01 (m, 3H), 3.87 (q,J=7.2 Hz, 2H), 3.33 (t, J=13.8 Hz, 2H), 3.05 (dt, J=12.8, 4.3 Hz, 1H),2.97 (dd, J=13.8, 3.6 Hz, 1H), 2.81-2.65 (m, 2H), 2.30 (qd, J=12.7, 4.3Hz, 1H), 1.69 (dd, J=13.5, 2.8 Hz, 1H), 0.93 (t, J=7.2 Hz, 3H).

Example 92 Synthesis of (±)-syn-Ethyl4-(pyridin-4-yl)piperidine-3-carboxylate (Compound 4kk)

Compound 4kk was prepared according to the method of Example 58 abovefrom 3kk in 81% yield using 10% Pd/C at 1 atm of H₂ and 65° C. for 24hours. ¹H NMR (300 MHz, CDCl₃) δ 8.58-8.53 (m, 2H), 7.12 (d, J=6.1 Hz,2H), 3.95 (qd, J=7.2, 2.2 Hz, 2H), 3.71-3.53 (m, 3H), 3.42 (dd, J=13.8,3.6 Hz, 1H), 3.37-3.27 (m, 1H), 2.48-2.35 (m, 1H), 2.11 (dd, J=14.4, 4.0Hz, 1H), 0.94 (t, J=7.2 Hz, 3H).

Example 93 Synthesis of (±)-syn-Ethyl4-(pyridin-3-yl)piperidine-3-carboxylate (Compound 4ll)

Compound 4ll was prepared according to the method of Example 58 abovefrom 3ll in 69% yield using 10% Pd/C at 1 atm of H₂ and 65° C. for 24hours. ¹H NMR (300 MHz, CDC₁₃) δ 8.51-8.40 (m, 2H), 7.53 (dt, J=8.0, 1.7Hz, 1H), 7.25-7.18 (m, 1H), 3.90 (q, J=7.2 Hz, 2H), 3.45-3.30 (m, 2H),3.13-2.97 (m, 2H), 2.85-2.72 (m, 2H), 2.38 (qd, J=12.7, 4.3 Hz, 1H),1.71 (dd, J=13.2, 2.8 Hz, 1H), 0.96 (t, J=7.2 Hz, 3H).

Example 94 Synthesis of (±)-syn-Ethyl4-(3-((tert-butoxycarbonyl)amino)phenyl)piperidine-3-carboxylate(Compound 4qq)

Compound 4qq was prepared according to the method of Example 58 abovefrom 3qq in 60% yield using 10% Pd/C at 1 atm of H₂ and 50° C. for 24hours. ¹H NMR (300 MHz, CDCl₃) δ 7.24-7.09 (m, 2H), 6.84 (d, J=7.15 Hz,1H), 3.89 (q, J=7.15 Hz, 2H), 3.39-3.23 (m, 2H), 3.06-2.89 (m, 2H),2.84-2.64 (m, 2H), 2.32 (qd, J=4.27, 12.70 Hz, 1H), 1.73-1.63 (m, 1H),1.50 (s, 9H), 0.95 (t, J=7.15 Hz, 3H).

Example 95 Synthesis of (±)-syn-Ethyl4-(3,4-difluorophenyl)piperidine-3-carboxylate (Compound 4ss)

Compound 4ss was prepared according to the method of Example 58 abovefrom 3ss in 60% yield using 10% Pd/C at 1 atm of H₂ and 50° C. for 24hours. ¹H NMR (300 MHz, CDCl₃) δ 7.13-6.96 (m, 2H), 6.95-6.86 (m, 1H),3.92 (q, J=7.15 Hz, 2H), 3.43-3.25 (m, 2H), 3.03-2.92 (m, 2H), 2.80-2.70(m, 2H), 2.28 (qd, J=4.40, 12.66 Hz, 1H), 2.17 (br. s., 2H), 1.65 (dq,J=3.03, 12.66 Hz, 1H), 1.00 (t, J=7.15 Hz, 3H).

Example 96 Synthesis of (±)-syn-Ethyl4-(4-nitrophenyl)piperidine-3-carboxylate (Compound 4tt)

Compound 4tt was prepared according to the methods of Examples 58 and71, above. ¹H NMR (300 MHz, CDCl₃) δ 8.21(dt, J=2.20, 8.81 Hz, 2H), 7.31(dt, J=2.20, 8.81 Hz, 2H), 3.95 (q, J=7.15 Hz, 2H), 3.85 (t, J=2.61 Hz,2H), 3.22 (t, J=5.92 Hz, 2H), 2.65-2.45 (m, 2H), 0.95 (t, J=7.02 Hz,3H).

Example 97 Synthesis of 4-(4-fluorophenyl)piperidine (Compound 15)

Compound 15 is referenced in Sakamuria Set al, Bioorg Med Chem Lett 11,495-500 (2001); incorporated by reference herein. Compound 15 wasprepared from 14 as a waxy white solid (167 mg, 56%) using the method ofExample 58 above. ¹H NMR (300 MHz, CDCl₃) δ 7.16 (dd, J=5.2, 8.8 Hz,2H), 6.97 (t, J=8.8 Hz, 2H), 3.82 (br. s, 1H), 3.16-3.33 (m, 2H), 2.76(dt, J=2.2, 12.1 Hz, 2H), 2.61 (tt, J=3.9, 12.10 Hz, 1H), 1.77-1.91 (m,2H), 1.70 (dt, J=3.9, 12.4 Hz, 2H).

Example 98 General Procedure for Synthesis of APQs

General Procedure: a 25 mL high-pressure tube was charged with compound4 (100 mg, 0.4 mmol), 1 (80 mg, 0.42 mmol), and toluene or CH₃CN (3 mL).The tube was sealed and heated to 110° C. for 2 days. The reactionmixture was concentrated and the residue was purified by flashchromatography eluting with 0-100% CH₂Cl₂/EtOAc [R_(f)≈0.3 (50%CH₂Cl₂/EtOAc)] to give compounds of series 5 as an off-white solid.

The ligands 5 were then converted to their hydrochloride salts prior tobiological testing. Compounds were dissolved in CHCl₃ (1 ml) and 1 N HCl(2 eq) was then added and the solution was stirred for 5 minutes. Thesolvent was removed under reduced pressure and the crude solid wasdissolved in water. After filtration and removal of the solvent bylyophilization, pure salts could be obtained in good yields.

Example 99 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-phenylpiperidine-3-carboxylate(Compound 5a)

Compound 5a was prepared from 4a and 1a as a white solid (59%) using themethod of Example 98 above. mp=169.0-170.0° C.; R_(f)=0.33 (75%EtOAc/CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃) δ 9.93 (br. s, 1H), 8.11 (dd,J=1.2, 8.1 Hz, 1H), 7.58 (dt, J=1.5, 7.2 Hz, 1H), 7.31-7.12 (comp, 6H),7.07 (d, J=8.4 Hz, 1H), 4.34-4.26 (m, 1H), 4.22-4.10 (m, 1H), 3.74 (dq,J=1.8, 7.2 Hz, 2H), 2.38 (dd, J=2.7, 8.4 Hz, 1H), 3.22 (d, J=10.8 Hz,1H), 2.98 (d, J=3.9 Hz, 1H), 2.85 (m, 1H), 2.71 (t, J=6.9 Hz, 2H), 2.60(dd, J=3.3, 11.1 Hz, 1H), 2.28 (dt, J=2.7, 10.8 Hz, 1H), 1.82 (dd,J=3.3, 12.6 Hz, 1H), 0.92 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ172.2, 162.4, 151.6, 143.4, 138.6, 135.0, 128.5, 128.0, 127.7, 126.1,123.4, 114.9, 114.7, 59.7, 56.9, 55.4, 53.8, 46.5, 42.1, 38.3, 26.8,14.0; Anal. Calcd for C₂₄H₂₇N₃O₄: C, 68.39; H, 6.46; N, 9.97; Found: C,68.23; H, 6.44; N, 9.90; MS (APCI, [M+H]⁺, m/z) 422.2.

Example 100 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(p-tolyl)piperidine-3-carboxylate(Compound 5b)

Compound 5b was prepared from 4b and 1a as an off-white solid (78%)using the method of Example 98 above. mp=212.5-213.0° C.; R_(f)=0.37(75% EtOAc/CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃) δ 10.46 (br. s, 1H), 8.11(d, J=7.8 Hz, 1H), 7.58 (dt, J=1.5, 6.6 Hz, 1H), 7.21 (t, J=6.6 Hz, 1H),7.15-7.05 (comp, 5H), 4.36-4.25 (m, 1H), 4.24-4.13 (m, 1H), 3.82-3.70(m, 2H), 3.37 (dd, J=3.0, 11.1 Hz, 1H), 3.20 (d, J=10.8 Hz, 1H), 2.96(d, J=3.3 Hz, 1H), 2.87-2.77 (m, 1H), 2.71 (t, J=7.5 Hz, 2H), 2.66-2.50(comp, 2H), 2.32-2.17 (comp, 4H), 1.84-1.77 (m, 1H), 0.94 (t, J=7.2 Hz,3H); Anal. Calcd for C₂₇H₃₁N₃O₆: C, 68.95; H, 6.71; N, 9.65; Found: C,68.90; H, 6.79; N, 9.65; MS (APCI, [M+H]⁺, m/z) 436.2.

Example 101 Synthesis of (±) syn-ethyl4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-1-(2-(2,4-dioxo-1,2-dihydro-quinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5c)

Compound 5c was prepared from 4c and 1a as a white solid (61%) using themethod of Example 98 above. mp=197.0-198.0° C.; R_(f)=0.20 (70%EtOAc/CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃) δ 9.53 (br. s, 1H), 8.10 (dd,J=1.5, 7.8 Hz, 1H), 7.58 (dt, J=1.5, 6.9 Hz, 1H), 7.21 (t, J=7.2 Hz,1H), 7.04 (d, J=7.8 Hz, 1H), 6.77-6.72 (comp, 3H), 4.30-4.10 (comp, 6H),3.77 (q, J=7.2 Hz, 2H), 3.34 (dd, J=2.4, 10.5 Hz, 1H), 3.18 (d, J=11.1Hz, 1H), 2.91 (d, J=3.6 Hz, 1H), 2.78-2.67 (comp, 3H), 2.58-2.46 (comp,2H), 2.25 (t, J=8.4 Hz, 1H), 1.77 (dd, J=2.7, 12.9 Hz, 1H), 0.97 (t,J=7.2 Hz, 3H); Anal. Calcd for C₂₆H₂₉N₃O₆: C, 65.12; H, 6.10; N, 8.76;Found: C, 64.83; H, 6.02; N, 8.54; MS (APCI, [M+H]⁺, m/z) 480.1.

5-HT1A hVMAT2 hVMAT2 [³H] 8-OH 5-HT2A [³H]DTBZ 5HT Uptake DPAT [¹²⁵I]DOIKi (nM) ± IC₅₀ (nM) ± Ki(nM) ± Ki (nM) ± SEM SEM SEM SEM >9 μM 156 ± 42ND ND

Example 102 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate (Compound 5d)

Compound 5d was prepared from 4d and 1a as an off-white solid (40%)using the method of Example 98 above (Note: the product can also bepurified by recrystallization in EtOAc): mp=173.0-175.0° C.; ¹H NMR (300MHz, CDCl₃) δ 10.29 (br. s., 1H), 8.11 (d, J=8.3 Hz, 1H), 7.59 (t, J=7.7Hz, 1H), 7.15-7.25 (m, 3H), 7.10 (d, J=8.3 Hz, 1H), 6.92 (t, J=8.8 Hz,2H), 4.24-4.40 (m, 1H), 4.09-4.24 (m, 1H), 3.75 (q, J=6.9 Hz, 2H), 3.38(d, J=11.0 Hz, 1H), 3.22 (d, J=11.0 Hz, 1H), 2.88-3.01 (m, 1H),2.77-2.88 (m, 1H), 2.66-2.77 (m, 2H), 2.57 (dd, J=2.5, 11.0 Hz, 2H),2.26 (td, J=2.5, 11.0 Hz, 1H), 1.69-1.93 (m, 1H), 0.93 (t, J=7.2 Hz,3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 171.8, 162.6, 162.4, 159.4, 150.7,140.2, 140.0, 135.4, 129.7, 129.6, 127.9, 122.9, 115.6, 115.0, 114.7,114.3, 59.5, 57.2, 55.3, 53.9, 46.0, 40.9, 37.9, 26.5, 14.3; Anal. Calcdfor C₂₄H₂₆N₃O₄F: C, 65.59; H, 5.96; N, 9.56; F, 4.32; Found: C, 65.51;H, 5.93; N, 9.49; F, 4.41; MS (APCI, [M+H]⁺, m/z) 440.2.

Example 103 Synthesis of (±)-syn-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate (Compound 5e)

Compound 5e was prepared from 4e and 1a as an off-white solid (40%)using the method of Example 98 above mp=170.6-171.4° C.; ¹H NMR (300MHz, CDCl₃) δ 9.91 (s, 1H), 8.12 (dd, J=1.65, 7.98 Hz, 1H), 7.59 (td,J=1.65, 7.71 Hz, 1H), 7.25-7.14 (m, 2H), 7.08 (d, J=7.98 Hz, 1H), 7.01(d, J=7.71 Hz, 1H), 6.96 (dt, J=2.17, 10.53 Hz, 1H), 6.89-6.79 (m, 1H),4.38-4.23 (m, 1H), 4.22-4.09 (m, 1H), 3.75 (q, J=7.15 Hz, 2H), 3.39 (dd,J=2.34, 11.14 Hz, 1H), 3.23 (d, J=11.28 Hz, 1H), 3.00-2.92 (m, 1H), 2.83(dt, J=4.16, 11.76 Hz, 3H), 2.71 (t, J=6.74 Hz, 2H), 2.63-2.49 (m, 2H),2.39-2.19 (m, 1H), 1.81 (dd, J=3.58, 12.93 Hz, 1H), 0.93 (t, J=7.15 Hz,3H); ¹³C NMR (75 MHz, CDCl₃) δ 171.9, 164.4, 162.4, 161.1, 151.8, 146.2,146.1, 138.7, 135.0, 129.4, 129.3, 128.5, 123.4, 123.2, 123.2, 114.9,114.8, 114.7, 114.5, 113.1, 112.8, 59.9, 56.9, 55.4, 53.7, 46.3, 41.8,38.3, 26.7, 14.0.; Anal. (C₂₄H₂₆N₃O₄F) C, H, N, F. MS (APCI, [M+H]⁺,m/z) 440.2.

Example 104 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-(trifluoromethyl)phenyl)piperidine-3-carboxylate(Compound 5f)

Compound 5f was prepared from 4f and 1a as an off-white solid (40%)using the method of Example 98 above. mp=211.5-212.0° C.; R_(f)=0.40(75% EtOAc/hexanes, 1% i-Pr—NH₂); ¹H NMR (300 MHz, CDCl₃) δ 9.02 (br. s,1H), 8.02 (d, J=8.1 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.50 (d, J=8.1 Hz,2H), 7.37 (d, J=8.1 Hz, 2H), 7.27-7.20 (m, 1H), 7.03 (d, J=7.8 Hz, 1H),4.33-4.24 (m, 1H), 4.17-4.09 (m, 1H), 3.70 (q, J=7.2 Hz, 2H), 3.39 (d,J=10.8 Hz, 1H), 3.26 (d, J=12.3 Hz, 1H), 3.00-2.94 (m, 1H), 2.91-2.83(m, 1H), 2.73-2.69 (m, 2H), 2.65-2.56 (comp, 2H), 2.29-2.19 (m, 1H),1.82 (d, J=13.2 Hz, 1H), 0.92 (t, J=7.2 Hz, 3H); Anal. Calcd forC₂₅H₂₆F₃N₃O₄: C, 61.34; H, 5.35; N, 8.58; F, 11.64; Found: C, 61.26; H,5.37; N, 8.37; F, 11.55; MS (APCI, [M+H]⁺, m/z) 490.1.

Example 105 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)piperidine-3-carboxylate(Compound 5g)

Compound 5g was prepared from 4g and 1a as an off-white solid (45%)using the method of Example 98 above. mp=181.0-182.0° C.; R_(f)=0.40(75% EtOAc/hexanes, 1% i-Pr—NH₂); ¹H NMR (300 MHz, CDCl₃) δ 9.50 (br. s,1H), 8.12 (dd, J=1.2, 8.1 Hz, 1H), 7.62-7.33 (comp, 5H), 7.19-7.23 (m,1H), 7.05 (d, J=8.1 Hz, 1H), 4.34-4.27 (m, 1H), 4.19-4.11 (m, 1H), 3.72(q, J=6.9 Hz, 2H), 3.41 (d, J=11.4 Hz, 1H), 3.26 (d, J=10.5 Hz, 1H),2.98 (d, J=3.3 Hz, 1H), 2.92-2.84 (m, 1H), 2.72 (t, J=7.2 Hz, 2H),2.65-2.54 (comp, 2H), 2.26 (dt, J=2.7, 11.1 Hz, 1H), 1.83 (dd, J=3.0,12.9 Hz, 1H), 0.91 (t, J=7.2 Hz, 3H); Anal. Calcd for C₂₅H₂₆F₃N₃O₄: C,61.34; H, 5.35; N, 8.58; F, 11.64; Found: C, 61.27; H, 5.33; N, 8.48; F,11.75; MS (APCI, [M+H]⁺, m/z) 490.1.

Example 106 Synthesis of (±) syn-ethyl4-(4-(dimethylamino)phenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5h)

Compound 5h was prepared from 4h and 1a as an off-white solid (55%)using the method of Example 98 above. mp=203.0-204.0° C.; R_(f)=0.38(75% EtOAc/hexanes, 1% i-Pr—NH₂); ¹H NMR (300 MHz, CDCl₃) δ 9.79 (br. s,1H), 8.11 (dd, J=1.5, 6.6 Hz, 1H), 7.57 (dt, J=1.5, 6.9 Hz, 1H), 7.20(t, J=7.5 Hz, 1H), 7.13 (d, J=8.7 Hz, 2H), 7.06 (d, J=8.4 Hz, 1H), 6.65(d, J=8.7 Hz, 2H), 4.33-4.14 (m, 2H), 3.82-3.73 (m, 2H), 3.33 (dd,J=2.7, 10.8 Hz, 1H), 3.17 (d, J=10.8 Hz, 1H), 2.95-2.87 (comp, 7H),2.83-2.65 (comp, 3H), 2.63-2.49 (comp, 2H), 2.28 (dt, J=2.4, 10.8 Hz,1H), 1.77 (dd, J=3.0, 12.6 Hz, 1H), 0.96 (t, J=7.2 Hz, 3H); ¹³C NMR (75MHz, CDCl₃) δ 172.5, 162.4, 151.8, 149.1, 138.7, 135.0, 131.5, 128.4,123.3, 114.9, 114.7, 112.6, 59.7, 56.7, 55.5, 53.9, 46.6, 41.4, 40.9,38.3, 27.3, 14.1; Anal. Calcd for C₂₆H₃₂N₄O₄: C, 66.45; H, 6.99; N,11.92; found: C, 66.31; H, 7.01; N, 11.78; MS (APCI, [M+H]⁺, m/z) 465.2.

Example 107 Synthesis of (±) syn-ethyl4-(4-carbamoylphenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5i)

Compound 5i was prepared from 4i and 1a as a white solid (73 mg, 38%)using the method of Example 98 above except use of DMF/1,4-dioxane (2/3,Vol/Vol) as solvent (Note: the product showed a poor solubility in manyorganic solvents and was purified by washing with EtOAc/MeOH (1/1,Vol/Vol)): ¹H NMR (300 MHz, DMSO-d₆) δ 11.41 (br. s, 1H), 7.92 (dd,J=1.2, 7.8 Hz, 1H), 7.88 (br. s, 1H), 7.75 (d, J=8.1 Hz, 2H), 7.64 (t,J=7.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.27 (br. s, 1H), 7.21-7.15(comp, 2H), 4.13-4.03 (m, 1H), 3.95-3.87 (m, 1H), 3.68-3.57 (m, 2H),3.23 (d, J=11.1 Hz, 1H), 3.14-3.09 (comp, 2H), 2.87-2.82 (m, 1H),2.58-2.39 (comp, 4H), 2.17-2.08 (m, 1H), 1.77 (d, J=9.6 Hz, 1H), 0.86(t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 171.8, 168.4, 162.4,150.7, 147.6, 140.0, 135.5, 132.3, 127.9, 127.6, 127.5, 123.0, 115.6,114.3, 59.6, 57.3, 55.3, 53.8, 45.9, 41.3, 37.9, 26.3, 14.3; Anal. Calcdfor C₂₅H₂₈N₄O₅: C, 64.64; H, 6.08; N, 12.06; Found: C, 64.14; H, 6.08;N, 11.97; MS (APCI, [M+H]⁺, m/z) 465.2.

Example 108 Synthesis of (±) syn-ethyl4-([1,1′-biphenyl]-4-yl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5j)

Compound 5j was prepared from 4j and 1a as an off-white solid (65%)using the general procedure described above. mp=219.0-220.0° C.;R_(f)=0.40 (75% EtOAc/hexanes, 1% i-Pr—NH₂); ¹H NMR (300 MHz, CDCl₃) δ9.77 (br. s, 1H), 8.12 (dd, J=1.2, 7.8 Hz, 1H), 7.61-7.27 (comp, 10H),7.21 (t, J=7.8 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 4.36-4.27 (m, 1H),4.23-4.14 (m, 1H), 3.40 (d, J=8.7 Hz, 1H), 3.24 (d, J=11.4 Hz, 1H), 3.01(d, J=3.6 Hz, 1H), 2.93-2.85 (m, 1H), 2.73 (t, J=6.9 Hz, 2H), 2.67-2.56(comp, 2H), 2.30 (dt, J=2.7, 10.8 Hz, 1H), 1.85 (dd, J=3.6, 12.9 Hz,1H), 0.94 (t, J=7.2 Hz, 3H); Anal. Calcd for C₂₇H₃₁N₃O₆: C, 68.95; H,6.71; N, 9.65; Found: C, 68.90; H, 6.79; N, 9.65; MS (APCI, [M+H]⁺, m/z)498.2.

Example 109 Synthesis of (±) syn-ethyl4-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5k)

Compound 5k was prepared from 4k and 1a as a viscous yellow oil (144 mg,58%) using the method of Example 98 above. R_(f)=0.10 (5% MeOH/CH₂Cl₂);¹H NMR (300 MHz, CDCl₃) δ 9.70 (br. s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.59(ddd, J=1.8, 7.2, 9.0 Hz, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.14 (dd, J=1.5,3.3 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.11 (br. s, 1H), 6.04 (t, J=3.3Hz, 1H), 4.31-4.14 (m, 2H), 3.86-3.75 (m, 2H), 3.54 (m, 1H), 3.29 (dd,J=3.6, 11.4 Hz, 1H), 3.15-3.07 (comp, 2H), 2.73-2.56 (comp, 3H), 2.46(m, 1H), 2.28 (m, 1H), 1.75 (d, J=12.6 Hz, 1H), 1.57 (s, 9H), 0.98 (t,J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.5, 162.4, 151.7, 149.5,138.6, 137.0, 135.0, 128.5, 123.3, 121.0, 114.9, 114.7, 112.5, 110.0,83.4, 59.6, 55.9, 55.5, 53.7, 44.0, 38.3, 35.6, 28.2, 27.9, 14.0.

Example 110 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-(ethoxycarbonyl)phenyl)piperidine-3-carboxylate(Compound 5l)

Compound 5l was prepared from 4l and 1a as an off-white solid (64%)using the method of Example 98 above. mp=213.0-213.5° C.; R_(f)=0.30(75% EtOAc/CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃) δ 9.71 (br. s, 1H), 8.11(dd, J=1.5, 8.1 Hz, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.58 (dt, J=1.2, 7.2Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 7.05 (d, J=8.4Hz, 1H), 4.37-4.26 (comp, 3H), 4.20-4.11 (m, 1H), 3.72 (q, J=7.2 Hz,2H), 3.40 (d, J=9.9 Hz, 1H), 3.24 (d, J=9.9 Hz,1H), 2.99 (d, J=3.3 Hz,1H), 2.82-2.75 (m, 1H), 2.71 (t, J=6.6 Hz, 2H), 2.65-2.54 (comp, 2H),2.25 (dt, J=2.7, 11.1 Hz, 1H), 1.84 (dd, J=3.0, 12.6 Hz, 1H), 1.36 (t,J=7.2 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H); Anal. Calcd for C₂₇H₃₁N₃O₆: C,65.71; H, 6.33; N, 8.51; Found: C, 65.94; H, 6.31; N, 8.48; MS (APCI,[M+H]⁺, m/z) 494.2.

Example 111 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(thiophen-2-yl)piperidine-3-carboxylate(Compound 5m)

Compound 5m was prepared from 4m and 1a as an off-white solid (158 mg,60%) using the method of Example 98 above (Note: the pure product wasobtained by recrystallization in EtOAc/Et₂O): mp=152.2-153.5° C.;R_(f)=0.31 (10% MeOH/CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃) δ 10.30 (br. s,1H), 8.10 (dd, J=1.2, 7.8 Hz, 1H), 7.59 (ddd, J=1.5, 6.6, 8.1 Hz, 1H),7.21 (t, J=6.6 Hz, 1H), 7.13-7.07 (comp, 2H), 6.88 (dd, J=3.3, 5.1 Hz,1H), 3.82 (d, J=3.3 Hz, 1H), 4.33-4.16 (m, 2H), 3.86 (q, J=6.9 Hz, 2H),3.38 (br. s, 1H), 3.09 (dd, J=6.9, 10.8, Hz, 1H), 3.01-2.96 (comp, 2H),2.83-2.71 (comp, 3H), 2.56-2.49 (m, 1H), 2.39-2.29 (m, 1H), 2.04-1.96(m, 1H), 1.01 (t, J=6.9 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) □172.1, 162.4,151.8, 146.3, 138.7, 135.1, 128.5, 126.4, 124.5, 123.4, 123.3, 115.0,114.7, 60.1, 55.5, 54.2, 52.0, 46.5, 38.3, 37.6, 30.0, 14.0; Anal. Calcdfor C₂₂H₂₅N₃O₄S: C, 61.81; H, 5.89; N, 9.83; S, 7.50; Found: C, 61.71;H, 5.79; N, 9.75; S, 7.29; MS (APCI, [M+H]⁺, m/z) 428.1.

Example 112 (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(5-methylthiophen-2-yl)piperidine-3-carboxylate(Compound 5n)

Compound 5n was prepared from 4n and 1a as an off-white solid (56 mg,20%) using the method of Example 98 above. R_(f)=0.20 (80%EtOAc/hexanes, 1% MeOH, 1% Et₃N); ¹H NMR (300 MHz, CDCl₃) δ 9.14 (br. s,1H), 8.10 (d, J=7.8 Hz, 1H), 7.58 (m, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.03(d, J=8.4 Hz, 1H), 6.59 (d, J=3.3 Hz, 1H), 6.52 (dd, J=1.2, 3.3 Hz, 1H),4.28-4.16 (m, 2H), 3.88 (q, J=7.2 Hz, 2H), 3.30 (br. s, 1H), 3.08-3.02(m, 1H), 2.95-2.90 (comp, 2H), 2.79-2.69 (comp, 3H), 2.53 (br. s, 1H),2.39 (s, 3H), 2.27 (br. s, 1H), 1.98-1.90 (m, 1H), 1.04 (t, J=7.2 Hz,3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.1, 162.3, 151.8, 143.6, 138.6, 137.6,134.9, 128.3, 124.3, 123.3, 114.9, 114.6, 59.9, 55.5, 53.8, 51.7, 46.2,38.2, 37.6, 30.0, 15.2, 14.0; Anal. Calcd for C₂₃H₂₇N₃O₄S: C, 62.56; H,6.16; N, 9.52; S, 7.26; Found: C, 62.49; H, 6.12; N, 9.37; S, 7.26; MS(APCI, [M+H]⁺, m/z) 442.2.

Example 113 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-(1-hydroxyethyl)phenyl)piperidine-3-carboxylate(Compound 5p)

Compound 5p was prepared from 4p and 1a as an off-white solid (13%)using the method of Example 98 above. mp=187.0-188.0° C.; R_(f)=0.15(70% EtOAc/hexanes, 1% i-Pr—NH₂); ¹H NMR (300 MHz, CDCl₃) δ 9.58 (br. s,1H), 8.11 (d, J=7.5 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.31-7.17 (comp,5H), 7.05 (d, J=7.8 Hz, 1H), 4.89-4.81 (m, 1H), 4.33-4.23 (m, 1H),4.21-4.09 (m, 1H), 3.73 (q, J=6.6 Hz, 2H), 3.37 (d, J=10.2 Hz, 1H), 3.21(d, J=10.5 Hz, 1H), 2.95 (br. s, 1H), 2.87-2.78 (m, 1H), 2.70 (t, J=6.6Hz, 2H), 2.65-2.51 (comp, 2H), 2.26 (t, J=11.1 Hz, 1H), 1.77 (d, J=3.3Hz, 1H), 1.45 (d, J=6.3 Hz, 3H), 0.93 (t, J=6.6 Hz, 3H); ¹³C NMR (75MHz, CDCl₃) δ 172.1, 162.4, 151.9, 143.5, 142.7, 138.7, 135.0, 128.4,127.8, 125.1, 123.3, 115.0, 114.7, 70.3, 59.7, 56.9, 55.4, 53.8, 46.4,41.9, 38.3, 26.9, 25.1, 14.0; Anal. Calcd for C₂₆H₃₁N₃O₅: C, 65.84; H,6.80; N, 8.85; Found: C, 65.88; H, 6.62; N, 8.91; MS (APCI, [M+H]⁺, m/z)466.2.

Example 114 Synthesis of (±)-syn-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)-4-(3-methoxyphenyl)piperidine-3-carboxylate (Compound 5q)

Compound 5q was prepared in 72% yield from 1a and 4q using the method ofExample 98 above. MP(HCl)=184.6-186.0° C. ¹H NMR (300 MHz, CDCl₃) δ 9.75(s, 1H), 8.11 (dd, J=1.65, 7.98 Hz, 1H), 7.63-7.53 (m, 1H), 7.24-7.13(m, 3H), 7.06 (d, J=8.26 Hz, 1H), 6.82-6.75 (m, 8H), 4.37-4.10 (m, 2H),3.78-3.72 (m, 2H), 3.75 (s, 3H), 3.35 (ddd, J=1.51, 3.23, 11.21 Hz, 1H),3.20 (d, J=12.38 Hz, 1H), 2.96-2.88 (m, 1H), 2.80 (dt, J=4.13, 11.56 Hz,1H), 2.74-2.64 (m, 2H), 2.64-2.50 (m, 2H), 2.33-2.18 (m, 1H), 1.77 (ddJ=3.30, 12.38 Hz, 1H), 0.94 (t, J=7.15 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃)δ 172.3, 162.4, 157.8, 151.7, 138.6, 135.5, 135.0, 128.7, 128.5, 123.3,114.9, 114.7, 113.4, 59.7, 56.8, 55.4, 55.3, 53.8, 46.5, 41.4, 38.3,27.1, 14.0. Anal. (C₂₇H₃₃N₃O₄; 1.2 HCl; 1.3 H₂O) C, H, N.

Example 115 Synthesis of (±)-syn-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)-4-(4-methoxyphenyl)piperidine-3-carboxylate (Compound 5r)

Compound 5r was prepared in 72% yield from 1a and 4r using the method ofExample 98 above. MP(HCl)=153-154° C. MP(HCl)=168.5-170° C. ¹H NMR (300MHz, CDCl₃) δ 9.63 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.58 (td, J=1.6, 7.7Hz, 1H), 7.24-7.13 (m, 3H), 7.05 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.8 Hz,2H), 4.35-4.22 (m, 1H), 4.22-4.09 (m, 1H), 3.76 (s, 3H), 3.81-3.67 (m,2H), 3.35 (d, J=11.0 Hz, 1H), 3.20 (d, J=11.3 Hz, 1H), 2.92 (q, J=3.3Hz, 1H), 2.86-2.75 (m, 1H), 2.75-2.65 (m, 2H), 2.57 (dd, J=3.2, 11.4 Hz,2H), 2.32-2.20 (m, 1H), 1.83-1.72 (m, 1H), 0.94 (t, J=7.2 Hz, 3H). ¹³CNMR (75 MHz, CDCl₃) δ 172.3, 162.4, 157.8, 151.7, 138.7, 135.5, 135.0,128.7, 128.5, 123.4, 114.9, 114.7, 113.4, 59.7, 56.8, 55.5, 55.3, 53.9,46.6, 41.4, 38.3, 27.1, 14.0. Anal. (C₂₅H₂₉N₃O₅.1.2HCl.1.3H₂O) C, H, N,Cl.

Example 116 Synthesis of (±)-syn-Ethyl4-(4-((tert-butoxycarbonyl)amino)phenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5s)

Compound 5s was prepared in 93% yield from 1a and 4s using the method ofExample 98 above. ¹H NMR (300 MHz, CDCl₃) δ 7.98 (dd, J=1.65, 7.98 Hz,1H), 7.56-7.41 (m, 1H), 7.30-7.20 (m, 2H), 7.20-7.04-7.20 (m, 3H), 7.00(d, J=7.98 Hz, 1H), 4.22-3.95 (m, 2H), 3.76-3.59 (m, 2H), 3.46-3.35 (m,4H), 3.32-3.14 (m, 2H), 3.05 (d, J=12.11 Hz, 1H), 2.86 (q, J=3.76 Hz,1H), 2.81-2.67 (m, 1H), 2.67-2.33 (m, 4H), 2.29-2.12 (m, 1H), 1.80-1.65(m, 1H), 1.41 (s, 9H), 0.88 (t, J=7.15 Hz, 3H).

Example 117 Synthesis of (±)-syn-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)-4-(4-ethylphenyl)piperidine-3-carboxylate (Compound 5t)

Compound 5t was prepared in 58% yield from 1a and 4t using the method ofExample 98 above. MP(HCl)=145-146° C. ¹H NMR (300 MHz, CDCl₃) δ 9.79 (s,1H), 8.11 (dd, J=1.1, 8.0 Hz, 1H), 7.58 (tq, J=1.6, 8.0 Hz, 1H),7.25-7.13 (m, 3H), 7.09 (d, J=2.5 Hz, 2H), 7.06 (d, J=2.7 Hz, 1H),4.37-4.09 (m, 2H), 3.75 (qd, J=6.9, 2.2 Hz, 2H), 3.37 (dd, J=3.0, 11.3Hz, 1H), 3.20 (d, J=11.0 Hz, 1H), 3.01-2.90 (m, 1H), 2.90-2.76 (m, 1H),2.71 (t, J=6.5 Hz, 2H), 2.64-2.51 (m, 4H), 2.27 (td, J=2.7, 10.9 Hz,1H), 1.80 (dd, J=3.2, 13.1 Hz, 1H), 1.19 (t, J=7.6 Hz, 3H), 0.93 (t,J=7.1 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 172.3, 162.4, 151.8, 141.9,140.6, 138.7, 135.0, 128.5, 127.7, 127.5, 123.3, 115.0, 114.7, 59.7,56.9, 55.5, 53.9, 46.5, 41.8, 38.3, 28.5, 15.6, 14.0. Anal. (C₂₆H₃₁N₃O₄;1.5 HCl; 1.2 H₂O) C, H, N, Cl.

Example 118 Synthesis of (±)-syn-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)-4-(4-isopropylphenyl)piperidine-3-carboxylate (Compound 5u)

Compound 5u was prepared in 52% yield from 1a and 4u using the method ofExample 98 above. MP(HCl)=153-154° C. ¹H NMR (300 MHz, CDCl₃) δ 9.26(br. s., 1H), 8.11 (d, J=7.7 Hz, 1H), 7.57 (t, J=7.4 Hz, 1H), 7.22-7.14(m, 3H), 7.11 (d, J=8.0 Hz, 2H), 7.04 (d, J=7.7 Hz, 1H), 4.36-4.21 (m,1H), 4.21-4.03 (m, 1H), 3.74 (q, J=7.1 Hz, 2H), 3.35 (d, J=12.4 Hz, 1H),3.20 (d, J=9.4 Hz, 1H), 2.94 (br. s., 1H), 2.89-2.75 (m, 2H), 2.72 (t,J=6.2 Hz, 2H), 2.58 (d, J=11.8 Hz, 2H), 2.35-2.13 (m, 1H), 1.80 (d,J=11.0 Hz, 1H), 1.13-1.26 (m, J=6.6 Hz, 6H), 0.92 (t, J=6.9 Hz, 3H). ¹³CNMR (75 MHz, CDCl₃) δ 172.2, 162.3, 151.4, 146.5, 140.7, 138.5, 135.0,128.5, 127.6, 126.1, 123.4, 114.7, 114.7, 59.7, 55.4, 53.9, 46.5, 41.9,38.3, 33.7, 26.9, 24.1, 24.1, 14.0. Anal. (C₂₇H₃₃N₃O₄; 1.25 HCl; 1.25H₂O) C, H, N.

Example 119 Synthesis of (±)-syn-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-phenethylpiperidine-3-carboxylate(Compound 5v)

Compound 5v was prepared in 38% yield from 1a and 4v using the method ofExample 98 above. MP(HCl)=140-141° C. ¹H NMR (300 MHz, CDCl₃) δ 10.7(br. s., 1H), 8.09 (dd, J=1.5, 8.1 Hz, 1H), 7.59 (ddd, J=1.6, 7.1, 8.3Hz, 1H), 7.31-7.17 (comp., 4H), 7.17-7.06 (comp., 4H), 4.39-4.12 (broadm., 2H), 4.11-3.87 (broad m, 2H), 2.93-2.73 (broad m, 1H), 2.73-2.57(broad m, 6H), 2.57-2.37 (broad m, 2H), 1.98-1.70 (broad m, 3H),1.70-1.51 (m, 2H), 1.14 (t, J=7.15 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ173.2, 162.4, 152.4, 142.3, 138.8, 135.0, 128.4, 128.3, 125.8, 123.3,115.2, 114.7, 60.0, 55.7, 45.0, 38.3, 33.8, 28.1, 14.3. Anal.(C₂₆H₃₁N₃O₄; 1.5 HCl; 0.25 H₂O) C, H, N.

Example 120 Synthesis of (±)-syn-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(2-fluorophenyl)piperidine-3-carboxylate(Compound 5x)

Compound 5x was prepared in 40% yield from 1a and 4x using the method ofExample 98 above. MP=182.8-183.6° C. ¹H NMR (300 MHz, CDCl₃) δ 9.98 (Br.S., 1H), 8.12 (dd, J=1.65, 7.98 Hz, 1H), 7.64-7.51 (m, 1H), 7.40-7.30(m, 1H), 7.24-7.17 (m, 1H), 7.17-6.88 (m, 4H), 4.39-4.23 (m, 1H), 4.16(dt, J=6.36, 12.86 Hz, 1H), 3.73 (q, J=7.15 Hz, 2H), 3.41 (d, J=10.73Hz, 1H), 3.28 (d, J=10.46 Hz, 1H), 3.16-3.00 (m, 2H), 2.77-2.66 (m, 2H),2.66-2.52 (m, 1H), 2.36-2.17 (m, 1H), 1.67 (d, J=11.01 Hz, 2H), 0.92 (t,J=7.15 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 172.2, 162.6, 162.4, 159.4,152.0, 138.7, 135.0, 130.2, 130.1, 129.7, 129.7, 129.7, 128.4, 127.7,127.6, 123.6, 123.6, 123.6, 123.4, 115.0, 114.9, 114.9, 114.7, 114.6,59.7, 57.2, 55.4, 54.1, 44.5, 38.3, 36.0, 26.0, 14.0. Anal.(C₂₄H₂₆N₃O₄F) C, H, N, F. MS (APCI, [M+H]⁺, m/z) 440.2.

Example 121 Synthesis of (±)-syn-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)-4-(m-tolyl)piperidine-3-carboxylate(Compound 5y)

Compound 5y was prepared in 31% yield from 1a and 4y using the method ofExample 98 above. MP(HCl)=148.5-150° C. ¹H NMR (300 MHz, CDCl₃) δ 9.91(br. s., 1H), 8.11 (dd, J=1.6, 8.0 Hz, 1H), 7.58 (ddd, J=1.4, 7.1, 8.3Hz, 1H), 7.24-7.02 (m, 5H), 6.96 (d, J=7.2 Hz, 1H), 4.37-4.09 (m, 2H),3.83-3.67 (m, 2H), 3.38 (dd, J=2.5, 11.0 Hz, 1H), 3.22 (d, J=11.8 Hz,1H), 3.02-2.93 (m, 1H), 2.88-2.77 (m, 1H),2.77-2.65 (m, 2H), 2.63-2.48(m, 2H), 2.29 (s, 3H), 2.34-2.19 (m, 1H), 1.91-1.75 (m, 1H), 0.93 (t,J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 172.2, 162.4, 151.8, 143.3,138.7, 137.4, 135.0, 128.6, 128.5, 127.9, 126.8, 124.7, 123.3, 115.0,114.7, 59.7, 56.9, 55.5, 53.9, 46.4, 46.4, 42.1, 38.3, 21.6, 14.0. Anal.(C₂₅H₂₉N₃O₄; 1.9 HCl; 0.1 H₂O) C, H, N.

Example 122 Synthesis of (±)-syn-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)-4-(o-tolyl)piperidine-3-carboxylate(Compound 5z)

Compound 5z was prepared in 38% yield from 1a and 4z using the method ofExample 98 above. MP(HCl)=174-175° C. ¹H NMR (300 MHz, CDCl₃) δ 10.73(br. s., 1H), 8.12 (dd, J=1.6, 8.0 Hz, 1H), 7.68-7.52 (m, 1H), 7.40-7.29(m, 1H), 7.24-6.99 (m, 5H), 4.45-4.11 (m, 2H), 3.76 (dq, J=3.6, 7.1 Hz,2H), 3.44 (d, J=11.6 Hz, 1H), 3.27 (d, J=11.6 Hz, 1H), 3.04-2.85 (m,2H), 2.85-2.63 (m, 3H), 2.63-2.52 (m, 1H), 2.31 (s, 3H), 2.40-2.18 (m,1H), 1.65 (d, J=14.6 Hz, 1H), 0.92 (t, J=7.2 Hz, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 172.1, 162.4, 152.2, 140.9, 138.8, 135.6, 135.0, 130.2, 128.4,128.3, 126.2, 125.7, 123.4, 115.2, 114.7, 59.7, 57.2, 55.6, 54.4, 44.0,39.6, 38.3, 27.1, 19.4, 14.0. Anal. (C₂₅H₂₉N₃O₄; 1.6 HCl; 1.0 H₂O) C, H,N.

Example 123 Synthesis of (±)-syn-Ethyl4-(3-(dimethylamino)phenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)piperidine-3-carboxylate (Compound 5aa)

Compound 5aa was prepared in 30% yield from 1a and 4aa using the methodof Example 98 above. MP(HCl)=179-180° C. ¹H NMR (300 MHz, CDCl₃) δ 9.95(s, 1H), 8.11 (dd, J=1.6, 8.0 Hz, 1H), 7.64-7.50 (m, 1H), 7.20 (t, J=7.4Hz, 1H), 7.16-7.02 (m, 2H), 6.68-6.61 (m, 2H), 6.55 (dd, J=2.5, 7.2 Hz,1H),4.38-4.06 (m, 2H), 3.78 (qd, J=7.1, 2.1 Hz, 5H), 3.40 (dd, J=3.0,12.7 Hz, 1H), 3.20 (d, J=11.01 Hz, 1H), 3.04-2.95 (m, 1H), 2.90 (s, 6H),2.71 (dd, J=5.2, 7.7 Hz, 5H), 2.60 (dd, J=3.6, 11.3 Hz, 2H), 2.39-2.17(m, 1H), 1.90-1.77 (m, 1H), 0.95 (t, J=7.0 Hz, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 172.5, 162.5, 152.2, 150.5, 144.2, 138.9, 135.0, 128.7, 128.3,123.3, 116.4, 115.2, 114.6, 112.5, 110.7, 59.8, 56.8, 55.6, 53.9, 46.4,42.5, 40.8, 38.3, 27.3, 14.0. Anal. (C₂₆H₃₂N₄O₄; 3 HCl; 2 H₂O) C, H, N.

Example 124 Synthesis of (±)-syn-Ethyl4-(2-(dimethylamino)phenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)piperidine-3-carboxylate (Compound 5bb)

Compound 5bb was prepared in 48% yield from 1a and 5bb using the methodof Example 98 above. MP(HCl)=208-209° C. ¹H NMR (300 MHz, CDCl₃) δ 10.29(s, 1H), 8.11 (dd, J=1.6, 8.0 Hz, 1H), 7.58 (ddd, J=1.6, 7.01, 8.3 Hz,1H), 7.35 (d, J=7.7 Hz, 1H), 7.24-7.09 (m, 4H), 7.07-6.97 (m, 1H),4.37-4.15 (m, 2H), 3.81-3.68 (m, 2H), 3.41 (dt, J=1.9, 8.5 Hz, 1H),3.34-3.20 (m, 3H), 2.84-2.62 (m, 3H), 2.61 (s, 6H), 2.62-2.53 (m, 1H),2.28 (tq, J=2.7, 11.3 Hz, 1H), 1.69-1.56 (m, 1H), 0.90 (t, J=7.2 Hz,3H). ¹³C NMR (75 MHz, CDCl₃) δ 173.0, 162.5, 153.1, 152.2, 152.1, 139.1,138.9, 135.0, 128.9, 128.3, 127.1, 124.3, 123.3, 121.0, 115.2, 114.7,59.5, 57.3, 55.7, 54.6, 46.1, 46.1, 44.6, 38.3, 37.6, 26.8, 14.0. Anal.(C₂₆H₃₂N₄O₄; 2 HCl; 2.75 H₂O) C, H, N, Cl.

Example 125 Synthesis of (±)-syn-Ethyl4-(3-azidophenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5cc)

To a cooled solution (0° C.) of 5qq (below) (70 mg, 0.16 mmol) in water(2 ml) was added conc. HCl (0.3 mL). The solution was stirred for 5minutes at 0° C. then NaNO₂ was added in 1 ml of water. The cooling bathwas removed and the solution was stirred for 1 hr. The reaction mixturewas cooled back to 0° C. and NaN₃ in 1 mL of water was added to themixture. Once again, the cooling bath was removed and the solution wasstirred for 1 hr at which time the reaction was quenched by the additionof sat. NaHCO₃, until pH=8. The mixture was then extracted with CH₂Cl₂(3×20 mL), dried over Na₂SO₄ and concentrated to afford pure compound5cc in 81% yield as an off-white foam. MP(HCl)=178-179° C. ¹H NMR (300MHz, CDCl₃) δ 10.23 (br. s., 1H), 8.11 (dd, J=1.65, 7.98 Hz, 1H), 7.59(ddd, J=1.51, 7.22, 8.32 Hz, 1H), 7.16-7.24 (m, 2H), 6.99-7.12 (m, 2H),6.90 (t, J=2.20 Hz, 1H), 6.79-6.87 (m, 1H), 4.09-4.37 (m, 2H), 3.69-3.81(m, 2H), 3.40 (dd, J=2.20, 11.28 Hz, 1H), 3.23 (d, J=11.28 Hz, 1H), 2.97(q, J=4.04 Hz, 1H), 2.82 (dt, J=4.13, 11.83 Hz, 1H), 2.71 (t, J=6.88 Hz,2H), 2.48-2.65 (m, 2H), 2.26 (td, J=2.89, 11.08 Hz, 1H), 1.81 (dd,J=3.03, 12.66 Hz, 1H), 0.95 (t, J=7.15 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃)δ Anal. (C₂₆H₃₂N₄O₄; 2 HCl; 2.75 H₂O) C, H, N, Cl.

Example 126 Synthesis of (±)-syn-Ethyl4-(3,4-dimethoxyphenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)piperidine-3-carboxylate (Compound 5dd)

Compound 5dd was prepared in 48% yield from 1a and 4dd using the methodof Example 98 above. MP(HCl)=154.5-155.5° C. ¹H NMR (300 MHz, CDCl₃) δ10.15 (br. s., 1H), 8.11 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H),7.24-7.14 (t, J=7.7 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.91-6.65 (m, 3H),4.44-4.09 (m, 1H), 3.83 (s, 6H), 3.99-3.66 (m, 2H), 3.37 (d, J=9.9 Hz,1H), 3.20 (d, J=11.3 Hz, 1H), 2.95 (br. s., 1H), 2.82 (d, J=10.5 Hz,1H), 2.77-2.67 (m, 2H), 2.67-2.45 (m, 2H), 2.41-2.17 (m, 1H), 1.82 (d,J=10.7 Hz, 1H), 0.96 (t, J=7.02 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) □172.4,162.4, 152.1, 148.5, 147.3, 138.8, 136.1, 135.0, 128.4, 123.4, 119.7,115.1, 114.7, 111.3, 110.8, 59.8, 56.8, 55.9, 55.9, 55.5, 53.9, 46.5,41.8, 38.3, 27.3, 14.1. Anal. (C₂₆H₃₁N₃O₆; 3 HCl; 2 H₂O) C, H, N.

Example 127 Synthesis of (±)-syn-Ethyl4-(3,4-dihydroxyphenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5ff)

Compound 5ff was prepared in 56% yield from 1a and 4ff using the methodof Example 98 above. MP(HCl)=167-168.5° C. ¹H NMR (300 MHz, DMSO-d₆) δ7.92 (dd, J=8.0, 1.7 Hz, 1H), 7.64 (td, J=7.7, 1.7 Hz, 1H), 7.24-7.12(m, 2H), 6.65 (d, J=2.2 Hz, 1H), 6.59 (m, J=8.0 Hz, 1H), 6.50 (td,J=8.3, 1.9 Hz, 10H), 4.14-3.89 (m, 2H), 3.76-3.59 (m, 1H), 3.15 (dd,J=10.5, 3.9 Hz, 1H), 3.02 (m, J=11.0 Hz, 1H), 2.94-2.81 (m, 1H),2.71-2.57 (m, 1H), 2.45-2.25 (m, 2H), 2.12 (t, J=9.1 Hz, 12H), 1.63 (d,J=13.5 Hz, 1H), 0.91 (t, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, DMSO-d₆) δ171.9, 162.4, 150.7, 145.0, 143.7, 140.0, 135.4, 134.9, 127.9, 123.0,118.7, 115.6, 115.5, 114.3, 59.4, 56.8, 55.4, 54.0, 46.2, 37.9, 27.0,14.4. Anal. (C₂₄H₂₇N₃O₆; 1 HCl; 2.5 H₂O) C, H, N.

Example 128 Synthesis of (±)-syn-Ethyl4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5gg)

Compound 5gg was prepared in 46% yield from 1a and 4gg using the methodof Example 98 above. MP(HCl)=178-179° C. ¹H NMR (300 MHz, CDCl₃) δ 9.55(s, 1H), 8.11 (dd, J=8.0, 1.7 Hz, 1H), 7.58 (ddd, J=8.3, 7.2, 1.7 Hz,1H), 7.21 (dt, J=7.2, 0.8 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.83-6.65 (m,3H), 4.34-4.21 (m, 1H), 4.20 (s, 4H), 4.19-4.10 (m, 1H), 3.78 (q, J=7.1Hz, 2H), 3.34 (dd, J=11.0, 3.3 Hz, 1H), 3.19 (d, J=11.3 Hz, 1H), 2.91(q, J=3.6 Hz, 1H), 2.83-2.62 (m, 3H), 2.61-2.40 (m, 2H), 2.26 (td,J=10.7, 2.5 Hz, 1H), 1.77 (dd, J=12.4, 3.3 Hz, 1H), 0.97 (t, J=7.2 Hz,3H). ¹³C NMR (75 MHz, CDCl₃) δ 172.3, 162.5, 152.2, 143.0, 141.8, 138.9,136.7, 135.0, 128.3, 123.3, 120.6, 116.7, 116.6, 115.2, 114.6, 64.4,59.8, 56.6, 55.5, 53.8, 46.4, 41.3, 38.2, 27.2, 14.1. Anal. (C₂₆H₂₉N₃O₆;1 HCl; 2.2 H₂O) C, H, N.

Example 129 Synthesis of Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(2-(trifluoromethyl)phenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 5hh)

Compound 5hh was prepared in 21% yield from 1a and 4hh using the methodof Example 98 above. MP(HCl)=153.5-154.5° C. ¹H NMR (300 MHz, CDCl₃) δ10.01 (br. s., 1H), 8.10 (dd, J=8.0, 1.7 Hz, 1H), 7.60 (td, J=8.0, 1.4Hz, 2H), 7.47 (t, J=8.0 Hz, 1H), 7.35 (m, J=7.7, 7.7 Hz, 1H), 7.22 (t,J=8.3 Hz, 1H), 7.14-7.04 (m, 2H), 4.46-4.22 (m, 2H), 3.83 (q, J=7.1 Hz,2H), 3.64 (d, J=16.8 Hz, 1H), 3.37 (dt, J=16.5, 3.0 Hz, 1H), 3.11-2.76(m, 2H), 2.72-2.58 (m, 1H), 2.53-2.41 (m, 2H), 0.79 (t, J=7.0 Hz, 3H).¹³C NMR (75 MHz, CDCl₃) δ 165.6, 162.6, 152.1, 145.8, 138.8, 135.1,131.5, 128.5, 128.3, 126.9, 126.6, 126.2, 126.1, 126.0, 123.4, 115.2,114.6, 60.1, 54.8, 52.9, 49.1, 38.1, 34.5, 13.5. Anal. (C₂₅H₂₄F₃N₃O₄;1.3 HCl; 1.1 H₂O) C, H, N.

Example 130 Synthesis of (±)-syn-ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-(trifluoromethoxy)phenyl)piperidine-3-carboxylate (Compound 5ii)

Compound 5ii was prepared in 51% yield from 1a and 4ll using the methodof Example 98 above. MP(HCl)=150-151.5° C. ¹H NMR (300 MHz, CDCl₃) δ10.02 (s, 1H), 8.16-8.04 (m, 1H), 7.59 (dt, J=8.3, 1.4 Hz, 1H),7.32-7.17 (m, 4H), 7.09 (d, J=8.3 Hz, 3H), 4.39-4.24 (m, 1H), 4.23-4.06(m, 1H), 3.74 (q, J=7.1 Hz, 2H), 3.39 (dd, J=10.5, 3.6 Hz, 1H), 3.23 (d,J=11.0 Hz, 1H), 3.02-2.89 (m, 1H), 2.83 (dt, J=11.8, 4.1 Hz, 1H), 2.71(t, J=6.9 Hz, 2H), 2.58 (qd, J=11.8, 3.6 Hz, 2H), 2.25 (td, J=10.7, 2.8Hz, 1H), 1.80 (dd, J=12.7, 2.8 Hz, 1H), 0.92 (t, J=7.2 Hz, 3H). ¹³C NMR(75 MHz, CDCl₃) δ 172.0, 162.4, 152.1, 147.5, 147.5, 142.2, 138.8,135.0, 129.0, 128.4, 123.4, 122.3, 120.5, 118.9, 115.1, 114.7, 59.9,56.9, 55.4, 53.8, 46.4, 41.7, 38.2, 26.8, 13.9. Anal. (C₂₅H₂₆F₃N₃O₅; 1.3HCl; 1.1 H₂O) C, H, N.

Example 131 Synthesis of (±)-syn-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(3-(trifluoromethoxy)phenyl)piperidine-3-carboxylate (Compound 5jj)

Compound 5jj was prepared in 64% yield from 1a and 4jj using the methodof Example 98 above. MP(HCl)=155-156° C. ¹H NMR (300 MHz, CDCl₃) δ 10.32(br. s., 1H), 8.12 (dd, J=8.0, 1.7 Hz, 1H), 7.59 (td, J=8.3, 1.4 Hz,1H), 7.25-7.15 (m, 2H), 7.14-7.05 (m, 2H), 7.01 (td, J=8.0, 1.1 Hz, 1H),4.39-4.13 (m, 2H), 3.75 (q, J=7.2 Hz, 2H), 3.40 (dd, J=11.4, 2.1 Hz,1H), 3.24 (m, J=11.0, 0.8 Hz, 1H), 2.97 (q, J=3.6 Hz, 1H), 2.85 (dt,J=11.5, 4.0 Hz, 1H), 2.72 (t, J=6.9 Hz, 2H), 2.65-2.44 (m, 2H), 2.26(td, J=11.0, 2.2 Hz, 1H), 1.89-1.76 (m, 2H), 0.92 (t, J=7.0 Hz, 3H). ¹³CNMR (75 MHz, CDCl₃) □171.9, 162.4, 152.0, 149.2, 149.1, 145.9, 138.7,135.0, 129.2, 128.4, 126.1, 123.4, 120.4, 118.5, 115.0, 114.7, 59.9,56.9, 55.4, 53.7, 46.3, 41.8, 38.3, 26.7, 13.9. Anal. (C₂₅H₂₆F₃N₃O₅; 1HCl; 1.5 H₂O) C, H, N.

Example 132 Synthesis of (±)-syn-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(pyridin-4-yl)piperidine-3-carboxylate(Compound syn-5kk)

Compound syn-5kk was prepared in 23% yield from 1a and 4kk using themethod of Example 98 above. MP(HCl)=210-211° C. ¹H NMR (300 MHz, CDCl₃)δ 8.48 (d, J=5.8 Hz, 2H), 8.12 (dt, J=7.8, 0.9 Hz, 1H), 7.64-7.52 (m,1H), 7.22 (d, J=7.7 Hz, 1H), 7.18 (d, J=6.3 Hz, 2H), 7.07 (d, J=8.0 Hz,1H), 4.40-4.23 (m, 1H), 4.23-4.04 (m, 1H), 3.71 (q, J=7.1 Hz, 2H), 3.40(d, J=12.1 Hz, 1H), 3.25 (d, J=11.3 Hz, 1H), 3.07-2.94 (m, 1H),2.86-2.75 (m, 1H), 2.75-2.65 (m, 2H), 2.57 (ddd, J=12.4, 11.6, 3.0 Hz,2H), 2.24 (m, J=10.7, 10.7, 2.5 Hz, 1H), 1.84 (dd, J=13.5, 3.6 Hz, 1H),0.91 (t, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 171.6, 162.4, 152.7,151.9, 149.4, 138.9, 135.0, 128.4, 123.3, 123.0, 115.0, 114.6, 60.0,57.1, 55.3, 53.4, 45.7, 41.3, 38.2, 26.0, 13.9. Anal. (C₂₃H₂₆N₄O₄; 2HCl; 2 H₂O) C, H, N.

Example 133 Synthesis of (±)-anti-Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(pyridin-4-yl)piperidine-3-carboxylate(Compound anti-5kk)

The title compound was isolated from the reaction of 1a and 4kk usingthe method of Example 98 above in 5% yield. ¹H NMR (300 MHz, CDCl₃) δ9.45 (s, 1H), 8.49 (dd, J=4.7, 1.4 Hz, 2H), 8.14 (dd, J=8.1, 1.5 Hz,1H), 7.62 (ddd, J=8.3, 7.2, 1.7 Hz, 1H), 7.29-7.22 (m, 4H), 7.12 (m,J=4.4, 1.7 Hz, 2H), 7.07 (d, J=8.0 Hz, 1H), 4.36-4.18 (m, 1H), 4.13 (q,J=7.0 Hz, 1H), 3.33 (d, J=7.7 Hz, 1H), 3.22 (d, J=11.8 Hz, 1H),2.93-2.68 (m, 3H), 2.39-2.15 (m, 4H), 1.79 (dd, J=8.4, 3.2 Hz, 2H),1.65-1.52 (m, 4H), 0.98 (t, J=7.0 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ172.8, 162.4, 152.7, 151.5, 149.9, 138.6, 135.2, 128.6, 123.5, 123.0,114.8, 114.7, 60.5, 58.9, 56.3, 55.3, 53.5, 48.3, 44.6, 38.3, 32.7,30.7, 23.5, 23.2, 22.3, 14.7, 14.0. Purity determined by LC/MS.

Example 134 Synthesis of (±)-syn-Ethyl4-(4-aminophenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)piperidine-3-carboxylate (Compound 5mm)

The title compound was prepared in 93% yield from 5s (above) by thefollowing procedure: A flask containing magnetic stir bar and carbamate5s was cooled to 0° C. and charged with trifluoroacetic acid (TFA). Theflask was removed from the ice-bath and stirred for 30 min at 0° C.,before concentrating to remove excess TFA. The residue was placed underhigh vacuum overnight to provide the pure product. MP(HCl)=263.5-265° C.¹H NMR (300 MHz, DMSO-d₆) δ 11.40 (s, 1H), 7.91 (dd, J=1.1, 8.0 Hz, 1H),7.65 (dt, J=7.7, 1.4 Hz, 1H), 7.11-7.26 (m, 2H), 6.90 (d, J=8.26 Hz,2H), 6.43 (d, J=8.53 Hz, 2H), 4.15-3.98 (m, 1H), 3.98-3.86 (m, 1H),3.79-3.58 (m, 2H), 3.14 (dd, J=2.2, 11.8 Hz, 1H), 3.02 (d, J=11.3 Hz,1H), 2.86 (d, J=3.6 Hz, 1H), 2.69-2.57 (m, 1H), 2.45-2.29 (m, 2H),2.19-2.06 (m, 1H), 1.61 (dd, J=2.7, 12.1 Hz, 1H), 0.90 (t, J=7.0 Hz,3H). ¹³C NMR (75 MHz, DMSO-d₆) δ 172.0, 162.4, 150.7, 147.0, 140.0,135.4, 131.0, 128.4, 127.9, 123.0, 115.6, 114.3, 114.0, 59.4, 56.8,55.4, 54.0, 46.3, 37.9, 27.0, 14.4. Anal. (C₂₄H₂₈N₄O₄; 2.1 HCl; 2.3 H₂O)C, H, N.

Example 135 Synthesis of (±)-Syn-Ethyl1-(2-(2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)ethyl)-4-(3,4-dichlorophenyl)piperidine-3-carboxylate (Compound syn-5nn) and (±)-Anti-Ethyl1-(2-(2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)ethyl)-4-(3,4-dichlorophenyl)piperidine-3-carboxylate (Compound anti-5nn)

Compounds syn-5nn and anti-5nn were produced according to the followingmethod:

The diasteromers were separated by prep-TLC eluting with 1% MeOH/CHCl₃(20 mg/plate, 3-5 elutions per plate).

Syn-5nn: Isolated 11 mg (15% impurity of anti-)¹H NMR (300 MHz, CDCl₃) δppm 9.46 (s, 1H), 8.11 (dd, J=8.0, 1.7 Hz, 1H), 7.64-7.54—(m, 1H),7.35-7.17 (m, 6H), 7.12-6.99 (m, 2H),4.37-4.21 (m, 1H),4.21-4.06 (m,1H), 3.73 (q, J=7.0 Hz, 2H), 3.43-3.29 (m, 1H), 3.24 (d, J=13.5 Hz, 1H),2.99-2.85 (m, 1H), 2.81-2.62 (m, 3H), 2.61-2.44 (m, 2H), 2.30-2.14 (m,1H), 1.84-1.68 (m, 1H), 0.94 (t, J=7.0 Hz, 3H). ¹³C NMR (76 MHz, CDCl₃)δ 171.7, 162.3, 151.5, 143.9, 138.6, 135.1, 135.0, 132.0, 129.9, 129.9,128.5, 127.2, 123.4, 114.8, 114.6, 114.6, 60.0, 57.1, 55.3, 53.6, 46.3,41.5, 38.2, 26.5, 14.0. MP(HCl salt)=144-146° C.

Anti-5nn: Isolated 20 mg pure. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.50 (s,1H), 8.13 (dd, J=8.0, 1.7 Hz, 1H), 7.69-7.54 (m, 1H), 7.38-7.17 (m, 3H),7.11-6.94 (m, 2H), 4.40-4.13 (m, 2H), 3.91 (qd, J=7.2, 1.7 Hz, 7H), 3.25(dd, J=29.2, 11.3 Hz, 6H), 2.85-2.63 (m, 4H), 2.39-2.14 (m, 2H),1.85-1.65 (m, 2H), 1.00 (t, J=7.2 Hz, 3H). ¹³C NMR (75 MHz,CHLOROFORM-d) δ 172.9, 162.4, 152.1, 144.0, 138.7, 135.2, 132.3, 130.5,130.4, 129.6, 128.5, 127.0, 123.6, 115.1, 114.7, 60.5, 56.4, 55.3, 53.6,48.9, 44.5, 38.3, 33.0, 14.1.

Example 136 Synthesis of (±) syn-ethyl4-(4-chlorophenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5oo)

Compound 5oo was prepared from 4oo and 1a as a white solid (118 mg, 38%)using the method of Example 98 above. mp=194.8-196.1° C.; ¹H NMR (300MHz, CDCl₃) δ 9.39 (br. s, 1H), 8.12 (d, J=6.6 Hz, 1H), 7.61-7.56 (m,1H), 7.20 (dd, J=11.4, 9.0 Hz, 4H), 7.04 (d, J=8.1 Hz, 1H), 4.34-4.24(m, 1H), 4.19-4.10 (m, 1H), 3.73 (q, J=7.2 Hz, 2H), 3.37 (d, J=9.3 Hz,1H), 3.26-3.19 (m, 1H), 2.92 (q, J=3.3 Hz, 1H), 2.79 (dt, J=4.2, 12.0Hz, 1H), 2.70 (t, J=6.6 Hz, 2H), 2.62-2.49 (comp, 2H), 2.25 (dt, J=2.7,10.5 Hz, 1H), 1.81-1.74 (m, 1H), 0.93 (t, J=7.2 Hz, 3H); ¹³C NMR (75MHz, CDCl₃) δ 171.9, 162.3, 151.5, 142.0, 138.6, 135.0, 131.8, 129.1,128.5, 128.1, 123.4, 114.8, 114.7, 59.8, 57.0, 55.4, 53.7, 46.4, 41.7,38.3, 26.7, 14.0; Anal. Calcd for C₂₄H₂₆ClN₃O₄: C, 63.22; H, 5.75; N,9.22; Cl, 7.78; Found: C, 63.25; H, 5.83; N, 9.25; Cl, 7.54.

Example 137 Synthesis of (±) syn-ethyl4-(3-chlorophenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5pp)

Compound 5pp was prepared from 4pp and 1a as a white solid (93 mg, 27%)using the method of Example 98 above. mp=161.8-162.9° C.; ¹H NMR (300MHz, CDCl₃) δ 8.89 (br. s, 1H), 8.12 (dd, J=1.5, 6.6 Hz, 1H), 7.62-7.56(m, 1H), 7.26-7.02 (comp, 4H), 7.01 (d, J=8.1 Hz, 1H), 4.32-4.24 (m,1H), 4.18-4.09 (m, 1H), 3.72 (q, J=7.2 Hz, 2H), 3.37 (d, J=11.1 Hz, 1H),3.25-3.22 (m, 1H), 2.93 (q, J=3.3 Hz, 1H), 2.78 (dt, J=4.2, 12.0 Hz,1H), 2.70 (t, J=6.9 Hz, 2H), 2.61-2.50 (comp, 2H), 2.22 (dt, J=2.7, 10.8Hz, 1H), 1.83-1.78 (m, 1H), 0.93 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 171.9, 162.3, 151.5, 145.6, 138.6, 135.0, 133.9, 129.2, 128.5,128.0, 126.2, 125.9, 123.4, 114.8, 114.7, 59.9, 57.0, 55.3, 53.7, 46.3,41.9, 38.2, 16.6, 14.0; Anal. Calcd for C₂₄H₂₆ClN₃O₄: C, 63.22; H, 5.75;N, 9.22; Cl, 7.78; Found: C, 63.11; H, 5.94; N, 9.04; Cl, 7.53.

Example 138 Synthesis of (±)-syn-Ethyl4-(3-((tert-butoxycarbonyl)amino)phenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5qq)

Compound 5qq was prepared from 4qq and 1a as a white solid (199 mg, 88%)using the method of Example 98 above. ¹H NMR (300 MHz, CDCl₃) δ 10.09(br. s., 1H), 8.11 (dd, J=1.65, 7.98 Hz, 1H), 7.62-7.52 (m, 1H),7.24-7.10 (m, 4H), 7.08 (d, J=7.98 Hz, 1H), 6.92 (d, J=7.15 Hz, 1H),4.37-4.15 (m, 1H), 4.11 (q, J=7.15 Hz, 2H), 3.80-3.67 (m, 2H), 3.37 (dd,J=2.06, 11.14 Hz, 1H), 3.21 (d, J=10.46 Hz, 1H), 3.01-2.90 (m, 1H),2.88-2.75 (m, 1H), 2.71 (t, J=6.88 Hz, 2H), 2.56 (ddd, J=0.83, 2.75,11.28 Hz, 2H), 2.31-2.17 (m, 1H), 1.78 (d, J=11.28 Hz, 1H), 1.50 (s,8H), 1.25 (t, J=7.15 Hz, 3H), 0.93 (t, J=7.15 Hz, 3H).

Example 139 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(1H-pyrrol-2-yl)piperidine-3-carboxylate (Compound 5rr)

Silica gel (1.07 g) was added to a solution of 5k (95 mg, 0.19 mmol) inCH₂Cl₂ (4 mL). The solvent was evaporated at room temperature, and theresidue was heated to 55° C. in a vacuum oven (2 mmHg) for 4 days. Thesilicagel was cooled to room temperature, and EtOAc (5 mL) was added.The mixture was filtered through a filter paper washing thoroughly withEtOAc (20 mL). The combined filtrate and washings were concentrated anddried under vacuum to give 5rr (41 mg, 52%) as an off-white solid:mp=202.0° C. (Dec.); ¹H NMR (300 MHz, CDCl₃) δ 9.05 (br. s, 1H), 8.80(br. s, 1H), 8.12 (d, J=7.2 Hz, 1H), 7.57 (dt, J=0.9, 7.5 Hz, 1H), 7.23(t, J=7.5 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H), 6.65 (m, 1H), 6.05 (dd,J=2.7, 5.7, 1H), 5.93 (br. s, 1H), 4.30-4.21 (m, 1H), 4.17-4.08 (m, 1H),3.95-3.84 (m, 2H), 3.26-3.22 (m, 1H), 3.11-3.07 (m, 1H), 2.99-2.95 (m,1H), 2.81 (dd, J=4.2, 8.1 Hz, 1H), 2.68 (t, J=6.9 Hz, 2H), 2.59 (dd,J=2.7, 12.0 Hz, 1H), 2.51-2.28 (comp, 2H), 1.75-1.69 (m, 1H), 1.07 (t,J=7.2 Hz, 3H); ¹H NMR (75 MHz, CDCl₃) δ 174.2, 162.4, 151.8, 138.6,135.1, 133.7, 128.5, 123.5, 116.9, 114.9, 114.7, 107.4, 106.2, 60.4,56.8, 55.5, 53.6, 46.5, 38.3, 36.9, 29.1, 14.1; Anal. Calcd forC₂₂H₂₆N₄O₄.0.25H₂O.0.08 EtOAc: C, 63.52; H, 6.38; N, 13.65; Found: C,63.67; H, 6.38; N, 13.18; MS (APCI, [M+H]⁺, m/z) 411.2.

Example 140 Synthesis of (±)-syn-Ethyl4-(3,4-difluorophenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5ss)

Compound 5ss was prepared from 4ss and 1a as a white solid (54% yield)using the method of Example 98 above. MP=196.6-198.4° C. ¹H NMR (300MHz, CDCl₃) δ 9.80 (Br. S. 1H), 8.11 (dd, J=1.65, 7.98 Hz, 1H),7.64-7.52 (m, 1H), 7.27-7.17 (t, J=7.71 Hz, 2H), 7.12-6.89 (m, 4H),4.37-4.077 (m, 2H), 3.75 (q, J=7.15 Hz, 2H), 3.45-3.34 (d, J=11.28 Hz,1H), 3.23 (d, J=11.56 Hz, 1H), 2.95-2.88 (m, 1H), 2.86-2.65 (m, 3H),2.62-2.44 (m, 2H), 2.23 (t, J=11.01 Hz, 3H), 1.77 (d, J=11.56 Hz, 1H),0.95 (t, J=7.15 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 171.8, 162.4, 151.8,140.6, 138.7, 135.0, 128.5, 123.5, 123.4, 116.8, 116.7, 116.5, 116.5,116.5, 114.9, 114.7, 59.9, 57.0, 55.3, 53.7, 46.4, 41.5, 38.2, 26.8,14.0. Anal. (C₂₄H₂₅F₂N₃O₄) C, H, N, F. MS (APCI, [M+H]⁺, m/z) 458.2.

Example 141 Synthesis of (±)-syn-Ethyl4-(4-nitrophenyl)-1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 5tt)

Compound 5tt was prepared from 4tt and 1a as a white solid (60% yield)using the method of Example 98 above. MP=216-217.4° C. ¹H NMR (300 MHz,CDCl₃) δ 8.84 (s, 1H), 8.17-8.03 (m, 3H), 7.65-7.49 (m, 1H), 7.48-7.36(m, 2H), 7.26-7.12 (m, 2H), 7.02 (d, J=7.98 Hz, 1H), 4.43-4.20 (m, 1H),4.20-4.03 (m, 1H), 3.69 (q, J=6.97 Hz, 2H), 3.43 (d, J=11.01 Hz, 1H),3.29 (d, J=11.28 Hz, 1H), 3.03-2.95 (m, 1H), 2.89 (dt, J=3.89, 11.76 Hz,1H), 2.79-2.51 (m, 4H), 2.24 (td, J=2.75, 11.28 Hz, 1H), 1.85 (dd,J=2.20, 12.66 Hz, 1H), 0.92 (t, J=7.15 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃)δ 171.5, 162.3, 151.5, 146.4, 138.5, 135.0, 128.6, 128.5, 123.5, 123.3,114.8, 114.7, 60.0, 57.3, 55.2, 53.6, 46.3, 42.2, 38.2, 26.3, 14.0.Anal. (C₂₄H₂₆N₄O₆) C, H, N. MS (APCI, [M+H]⁺, m/z) 467.2.

Example 142 Synthesis of (±)-syn-Ethyl1-(3-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)propyl)-4-(4-fluorophenyl)piperidine-3-carboxylate

The compound was prepared from 4d and3-(3-chloropropyl)quinazoline-2,4(1H,3H)-dione (Chem J W et al, J HetChem 25, 1103-1105 (1988); incorporated by reference herein) as a whitesolid (54% yield) using the method of Example 98 above. MP=171.8-172.4°C. ¹H NMR (300 MHz, CDCl₃) δ 9.27 (s, 1H), 8.13 (dd, J=1.65, 7.98 Hz,1H), 7.65-7.54 (m, 1H), 7.29-7.18 (m, 4H), 7.07 (d, J=7.98 Hz, 1H), 6.95(t, J=8.81 Hz, 2H), 4.17-3.87 (m, 4H), 3.39-3.23 (m, 1H), 3.04 (d,J=10.46 Hz, 1H), 2.99-2.90 (m, 1H), 2.83 (dt, J=4.02, 11.76 Hz, 1H),2.66-2.34 (m, 4H), 2.15 (td, J=3.16, 11.08 Hz, 1H), 2.00-1.83 (m, 2H),1.79 (d, J=12.38 Hz, 1H), 1.06 (t, J=7.15 Hz, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 172.3, 163.0, 162.4, 159.7, 152.0, 139.1, 139.1, 139.1, 138.6,135.0, 129.2, 129.2, 129.2, 129.1, 128.5, 123.4, 115.0, 114.9, 114.7,114.6, 60.0, 56.1, 55.9, 53.9, 46.4, 41.7, 39.6, 27.0, 25.3, 14.2 Anal.(C₂₅H₂₈FN₃O₄) C, H, N. MS (APCI, [M+H]⁺, m/z) 454.2.

Example 143 Synthesis of (±)-syn-Ethyl1-(4-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)butyl)-4-(4-fluorophenyl)piperidine-3-carboxylate

The compound was prepared from 4d and3-(3-chlorobutyl)quinazoline-2,4(1H,3H)-dione (Chem et al, 1988 supra)as a white solid (40% yield) using the general procedure describedabove. MP=148.5-149.7° C. ¹H NMR (300 MHz, CDCl₃) δ 9.27 (s, 1H), 8.13(dd, J=1.65, 7.98 Hz, 1H), 7.65-7.54 (m, 1H), 7.29-7.18 (m, 4H), 7.07(d, J=7.98 Hz, 1H), 6.95 (t, J=8.81 Hz, 2H), 4.17-3.87 (m, 4H),3.39-3.23 (m, 1H), 3.04 (d, J=10.46 Hz, 1H), 2.99-2.90 (m, 1H), 2.83(dt, J=4.02, 11.76 Hz, 1H), 2.66-2.34 (m, 4H), 2.15 (td, J=3.16, 11.08Hz, 1H), 2.00-1.83 (m, 2H), 1.79 (d, J=12.38 Hz, 1H), 1.06 (t, J=7.15Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 172.3, 163.0, 162.4, 159.7, 152.0,139.1, 139.1, 139.1, 138.6, 135.0, 129.2, 129.2, 129.2, 129.1, 128.5,123.4, 115.0, 114.9, 114.7, 114.6, 60.0, 56.1, 55.9, 53.9, 46.4, 41.7,39.6, 27.0, 25.3, 14.2 Anal. (C₂₆H₃₀FN₃O₄) C, H, N,F. MS (APCI, [M+H]⁺,m/z) 454.2.

Example 144 Synthesis of (±)-syn-Ethyl1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate

The compound was prepared according to the general procedure above in57% yield from 4d and N-(2-Bromoethyl)phthalimide. MP(HCl)=104.5-105.5°C. ¹H NMR (300 MHz, CDCl₃) δ 7.85-7.80 (m, 2H), 7.71-7.66 (m, 2H), 7.22(dd, J=8.3, 5.8 Hz, 7H), 6.93 (t, J=8.8 Hz, 2H), 3.92-3.70 (m, 2H), 3.63(td, J=7.3, 3.6 Hz, 2H), 3.27 (ddd, J=11.4, 3.5, 1.9 Hz, 1H), 3.21-3.10(m, 1H), 2.93-2.84 (m, 1H), 2.78 (dt, J=11.8, 4.2 Hz, 1H), 2.65 (ddd,J=7.4, 5.7, 2.1 Hz, 2H), 2.51 (dd, J=11.0, 3.3 Hz, 2H), 2.18 (td,J=10.9, 2.9 Hz, 1H), 1.87-1.70 (m, 2H), 0.92 (t, J=7.2 Hz, 3H). ¹³C NMR(75 MHz, CDCl₃) δ 171.8, 168.4, 162.9, 159.7, 139.1, 139.0, 133.9,132.3, 129.2, 129.1, 123.2, 114.9, 114.6, 59.7, 56.9, 55.6, 53.4, 46.5,41.6, 35.4, 26.7, 14.0. Anal. (C₂₄H₂₅FN₂O₄; 1 HCl; 1.3 H₂O) C, H, N.

Example 145 Synthesis of (±)-syn-Ethyl1-(2-(6-bromo-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate

The compound was prepared in 51% yield from 4d and 1c. MP(HClsalt)=167-168° C. ¹H NMR (300 MHz, CDCl₃) δ 8.21 (br. s., 1H), 7.64 (dd,J=2.48, 8.53 Hz, 1H), 7.23-7.11 (m, 2H), 7.06-6.84 (m, 3H), 4.35-4.08(m,2H), 3.74 (q, J=7.15 Hz, 2H), 3.44-3.29 (m, 1H), 3.27-3.11 (m,1H),2.98-2.87 (m, 1H), 2.82 (dt, J=4.09, 11.63 Hz, 1H), 2.76-2.63 (m,2H),2.63-2.44 (m, 2H), 2.24 (td, J=2.20, 11.01 Hz, 1H), 1.78 (dd,J=3.58, 12.11 Hz, 1H), 0.94 (t, J=7.15 Hz, 3H). ¹³C NMR (76 MHz, CDCl₃)δ 172.2, 163.0, 161.2, 159.7, 151.8, 138.9, 138.9, 138.9, 137.8, 137.7,130.9, 129.1, 129.1, 129.0, 129.0, 116.9, 116.1, 116.0, 114.9, 114.7,77.5, 77.3, 77.1, 76.7, 59.9, 56.7, 55.3, 53.8, 46.5, 41.5, 38.4, 26.9,14.0. Anal. (C₂₄H₂₅FN₃O₄; 1 HCl; 1.25 H₂O) C, H, N.

Example 146 Synthesis of (±)-syn-Ethyl1-(2-(6,8-dibromo-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate

The title compound was prepared in 58% yield from 4d and 1d. ¹H NMR (300MHz, CDCl₃) δ 8.21 (d, J=2.20 Hz, 1H), 8.05 (s, 1H), 7.91 (d, J=2.20 Hz,1H), 7.24-7.14 (m, 2H), 6.94 (t, J=8.67 Hz, 2H), 4.31-4.02 (m, 2H),3.86-3.66 (m, 2H), 3.31 (ddd, J=1.79, 3.51, 11.49 Hz, 1H),3.22-3.08 (m,1H), 2.90 (t, J=3.85, Hz, 1H), 2.80 (dt, J=4.13, 12.11 Hz, 4H), 2.67 (t,J=6.74 Hz, 2H), 2.42-2.61 (m, 2H), 2.22 (td, J=2.75, 11.01 Hz, 1H), 1.78(dd, J=3.44, 12.80 Hz, 1H), 0.97 (t, J=7.15 Hz, 3H). ¹³C NMR (76 MHz,CDCl₃) δ 171.9, 162.9, 160.4, 159.7, 149.4, 139.8, 139.1, 139.0, 139.0,135.6, 130.8, 129.2, 129.1, 129.1, 117.0, 115.7, 114.9, 114.6, 109.1,59.7, 56.8, 55.1, 53.7, 46.5, 41.6, 38.7, 26.9, 14.0.

Example 147 General Synthesis of Compounds of Series 6 from Compounds ofSeries 5

Anhydrous K₂CO₃ (0.43 mmol) and alkyl halide (0.2 mmol) were added to asolution of 5 (0.15 mmol) in anhydrous DMF (1.5 mL). The resultingmixture was stirred at room temperature for 2 h, and EtOAc (8 mL) andwater (3 mL) were added. The organic layer was separated, dried(Na₂SO₄), and concentrated. The residue was purified by flashchromatography eluting with 80% EtOAc/hexanes (1% Et₃N, 1% MeOH) to give6.

Example 148 Synthesis of (±) syn-ethyl4-(4-fluorophenyl)-1-(2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 6a)

Compound 6a was prepared according to the method of Example 147 abovefrom 5d and methyl iodide in 93% yield. mp=131.1-133.0° C.; ¹H NMR (300MHz, CDCl₃) δ 8.21 (dd, J=1.8, 8.1 Hz, 1H), 7.66 (ddd, J=1.8, 7.2, 8.4Hz, 1H), 7.27-7.20 (comp, 4H), 6.94 (t, J=8.7 Hz, 2H), 4.32-4.13 (m,2H), 3.72 (q, J=7.2 Hz, 2H), 3.61 (s, 3H), 3.37 (d, J=11.4 Hz, 1H), 3.21(d, J=10.8 Hz, 1H), 2.90 (dd, J=3.6, 4.8 Hz, 1H), 2.80 (dt, J=3.9, 11.7Hz, 1H), 2.70-2.65 (m, 2H), 2.62-2.52 (comp, 2H), 2.23 (dt, J=2.7, 10.8Hz, 1H), 1.79 (dd, J=3.3, 12.6 Hz, 1H), 0.94 (t, J=7.2 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃) δ 171.9, 161.8, 161.3 (d, J=242.2 Hz), 151.1, 140.7,139.2, 135.1, 129.2 (d, J=7.4 Hz), 128.9, 122.9, 115.6, 114.7 (d, J=21.2Hz), 113.6, 59.7, 57.0, 55.3, 53.9, 46.5, 41.7, 39.1, 30.8, 26.8, 14.0;Anal. Calcd for C₂₅H₂₈FN₃O₄: C, 66.21; H, 6.22; F, 4.19; N, 9.27; Found:C, 66.14; H, 6.30; F, 4.04; N, 9.15; MS (APCI, [M+H]⁺, m/z) 454.2

Example 149 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1-propyl-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate(Compound 6b)

Compound 6b was prepared according to the method of Example 147 aboveusing 5d and 1-bromopropane in 67% yield.: mp=96.8-97.7° C.; Rf=0.42(80% EtOAc/hexanes, 1% Et₃N, 1% MeOH); ¹H NMR (300 MHz, CDCl₃) δ 8.20(dd, J=1.5, 7.5 Hz, 1H), 7.64 (ddd, J=1.2, 7.5, 8.4 Hz, 1H), 7.27-7.15(comp, 4H), 6.94 (t, J=8.7 Hz, 2H), 4.33-4.10 (m, 2H), 4.1-4.04 (m, 2H),3.74 (dq, J=1.2, 7.2 Hz, 2H), 3.41-3.34 (m, 1H), 3.20 (d, J=11.7 Hz,1H), 2.90 (q, J=3.3 Hz, 1H), 2.79 (dt, J=3.6, 11.1, 1H), 2.68 (t, J=7.2Hz, 2H), 2.60-2.51 (comp, 2H), 2.25 (dt, J=3.3, 11.1 Hz, 1H), 1.83-1.71(m, 2H), 1.04 (t, J=7.5 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H); ¹³C NMR (75MHz, CDCl₃) δ 171.9, 161.8, 161.3 (d, J=241.0), 150.9, 140.0, 139.2,135.0, 129.2, 122.7, 115.8, 114.8 (d, J=20.6 Hz), 113.6, 59.7, 56.9,55.3, 53.8, 46.5, 45.4, 41.7, 39.0, 26.9, 20.7, 14.0, 11.3; Anal. Calcdfor C₂₇H₃₂FN₃O₄: C, 67.34; H, 6.70; F, 3.95; N, 8.73; Found: C, 67.57;H, 6.66; F, 3.81; N, 8.69; MS (APCI, [M+H]⁺, m/z) 482.2.

Example 150 Synthesis of (±) syn-ethyl1-(2-(1-benzyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate(Compound 6c)

Compound 6c was prepared according to the method of Example 147 aboveusing 5d and benzyl bromide in 46% yield.: mp=134.9-136.4° C.; Rf=0.61(80% EtOAc/hexanes, 1% Et₃N, 1% MeOH); ¹H NMR (300 MHz, CDCl₃) δ 8.20(d, J=7.8 Hz, 1H), 7.50 (dt, J=1.2, 7.2 Hz, 1H), 7.37-7.17 (comp, 3H),7.08 (d, J=8.4 Hz, 1H), 6.95 (t, J=9.0 Hz, 2H), 5.37 (dd, J=16.8, 25.5Hz, 2H), 4.39-4.32 (m, 1H), 4.27-4.20 (m, 1H), 3.70 (q, J=7.2 Hz, 2H),3.36 (d, J=11.4 Hz, 1H), 3.23 (d, J=10.2 Hz, 1H), 2.91 (d, J=3.6 Hz,1H), 2.81-2.71 (comp, 3H), 2.63-2.50 (comb, 2H), 2.26 (dt, J=3.3, 8.1Hz, 1H), 1.78 (dd, J=3.3, 9.9 Hz, 1H), 0.91 (t, J=7.2 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃) δ 172.0, 161.8, 161.3 (d, J=241.6 Hz), 151.5, 140.1,139.2, 135.8, 135.0, 129.2, 129.1, 127.7, 126.5, 123.0, 115.8, 114.9,114.5 (d, J=12.0 Hz), 59.7, 57.0, 55.3, 53.7, 47.5, 46.5, 41.6, 39.2,26.9, 14.0; Anal. Calcd for C₃₁H₃₂FN₃O₄: C, 70.30; H, 6.09; N, 7.93;Found: C, 70.17; H, 6.10; N, 7.74; MS (APCI, [M+H]⁺, m/z) 530.2.

Binding Data:

5-HT1A hVMAT2 hVMAT2 [³H] 8-OH 5-HT2A [³H]DTBZ 5HT Uptake DPAT [¹²⁵I]DOIKi (nM) ± IC₅₀ (nM) ± Ki(nM) ± Ki (nM) ± SEM SEM SEM SEM >7 μM 270 ± 53ND ND

Example 151 (±)-syn Ethyl4-(3-fluorophenyl)-1-(2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 6d)

5-HT1A hVMAT2 hVMAT2 [³H] 8-OH 5-HT2A [³H]DTBZ 5HT Uptake DPAT [¹²⁵I]DOIKi (nM) ± IC₅₀ (nM) ± Ki(nM) ± Ki (nM) ± SEM SEM SEM SEM >9 μM 89 ±12 >10 μM ND

Compound 6d was prepared according to the method of Example 147 aboveusing 5e and methyl iodide in 67% yield.: mp=101.2-102.5° C.; Rf=0.32(80% EtOAc/hexanes, 1% Et₃N, 1% MeOH); ¹H NMR (300 MHz, CDCl₃) δ 8.20(dd, J=1.5, 7.8 Hz, 1H), 1.65 (ddd, J=1.5, 6.9, 8.4 Hz, 1H), 7.27-7.17(comp, 3H), 7.06-6.97 (comp, 2H), 6.85 (dt, J=2.7, 7.8 Hz, 1H),4.35-4.25 (m, 1H), 4.22-4.13 (m, 1H), 3.72 (q, J=7.2 Hz, 2H), 3.60 (s,3H), 3.41-3.35 (m, 1H), 3.22 (d, J=11.1 Hz, 1H), 2.95 (q, J=3.3 Hz, 1H),2.81 (dt, J=3.6, 12.3 Hz, 1H), 2.68 (t, J=6.9 Hz, 2H), 2.60-2.53 (comp,2H), 2.24 (dt, J=3.0, 11.1 Hz, 1H), 1.81 (dd, J=3.3, 12.9 Hz, 1H), 0.94(t, J=7.2 Hz, 3H); NMR (75 MHz, CDCl₃) δ 171.8, 162.8 (d, J=242.8 Hz),161.8, 151.1, 146.2 (d, J=6.9 Hz), 140.7, 135.1, 129.2 (d, J=8.0 Hz),129.0, 123.3, 122.9, 115.7, 114.7 (d, J=21.2 Hz), 113.6, 112.8 (d,J=21.2 Hz), 59.7, 57.0, 55.3, 53.7, 46.3, 41.9, 39.1, 30.8, 26.6, 14.0;Anal. Calcd for C₂₅H₂₈FN₃O₄: C, 66.21; H, 6.22; F, 4.19; N, 9.27; Found:C, 66.04; H, 6.32; F, 4.09; N, 9.22; MS (APCI, [M+H]⁺, m/z) 454.2.

Example 152 Synthesis of (±)-syn-ethyl1-(2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(thiophen-2-yl)piperidine-3-carboxylate(Compound 6e)

The title compound was prepared from 5m as a white solid (43 mg, 79%)using the method of Example 147 above. mp=99.5-100.7° C.; Rf=0.44 (80%EtOAc/hexanes, 1% Et₃N, 1% MeOH); ¹H NMR (300 MHz, CDCl₃) δ 8.20 (dd,J=1.5, 7.8 Hz, 1H), 7.66 (ddd, J=1.8, 6.9, 8.7 Hz, 1H), 7.28-7.23 (m,1H), 7.18 (d, J=8.4 Hz, 1H), 7.11 (dd, J=1.2, 5.1 Hz, 1H), 6.89 (dd,J=3.6, 4.8 Hz, 1H), 6.86-6.84 (m, 1H), 4.31-4.17 (m, 2H), 3.84 (q, J=7.2Hz, 2H), 3.60 (s, 3H), 3.35 (br. s, 1H), 3.11 (dd, J=6.0, 11.1 Hz, 1H),2.99-2.94 (comp, 2H), 2.77-2.65 (comp, 3H), 2.54-2.44 (m, 1H), 2.42-2.30(m, 1H), 2.02-1.91 (m, 1H), 1.68 (br. s, 1H), 1.02 (t, J=7.2 Hz, 3H);¹³C NMR (75 MHz, CDCl₃) δ 172.0, 161.8, 151.1, 146.5, 140.7, 135.1,129.0, 126.4, 124.4, 123.2, 122.9, 115.6, 113.6, 60.0, 55.5, 54.5, 52.1,46.5, 39.1, 37.7, 30.8, 29.8, 14.1; Anal. Calcd for C₂₃H₂₇N₃O₄S: C,62.56; H, 6.16; S, 7.26, N, 9.52; Found: C, 62.38; H, 6.17; S, 7.19; N,9.58; MS (APCI, [M+H]⁺, m/z) 442.2.

Example 153 Synthesis of Compounds of Series 7

A 25 mL high-pressure tube was charged with compound 4 (118 mg, 0.47mmol), 1b (91 mg, 0.47 mmol), anhydrous DMF (1 mL), and anhydrous1,4-dioxane (1 mL). The tube was sealed and heated to 90° C. for 20 h.The mixture was concentrated and the residue was purified by flashchromatography eluting with 80% EtOAc/hexanes (1% MeOH, 1% Et3N) to give7.

Example 154 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate(Compound 7a)

Compound 7a was prepared from Compound 4d (122 mg, 57%) as an off-whitesolid using the method of Example 153 above. mp=198.8-201.4° C.;R_(f)=0.10 (80% EtOAc/hexanes, 1% MeOH, 1% Et₃N); ¹H NMR (300 MHz,CDCl₃) δ 7.27-7.19 (comp, 3H), 6.93 (t, J=8.7 Hz, 2H), 6.77 (d, J=5.7Hz, 1H), 4.28-4.19 (m, 1H), 4.15-4.06 (m, 1H), 3.77 (q, J=7.2 Hz, 2H),3.35 (dd, J=3.3, 10.5 Hz, 1H), 3.23 (d, J=11.7 Hz, 1H), 2.92 (d, J=3.3Hz, 1H), 2.81 (dt, J=3.9, 11.4 Hz, 1H), 2.70 (t, J=6.9 Hz, 2H),2.60-2.55 (comp, 2H), 2.24 (dt, J=3.6, 11.7 Hz, 1H), 1.80 (dd, J=3.0,12.3 Hz, 1H), 0.97 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.2,161.2 (d, J=242.2 Hz), 158.8, 151.9, 149.5, 139.1, 129.1 (d, J=7.4 Hz),123.4, 116.1, 115.9, 114.7 (d, J=20.6 Hz), 59.9, 56.9, 55.4, 53.6, 46.5,41.5, 38.1, 26.9, 14.0; Anal. Calcd for C₂₂H₂₄FN₃O₄S: C, 59.31; H, 5.43;N, 9.43; S, 7.20; F, 4.26; Found: C, 59.38; H, 5.49; N, 9.20; S, 7.00;F, 4.01; MS (APCI, [M+H]⁺, m/z) 446.1.

Example 155 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)ethyl)-4-(3-fluorophenyl)piperidine-3-carboxylate(Compound 7b)

Compound 7b was prepared from 4e and 1b as a white solid (137 mg, 60%)using the method of Example 153 above. mp=153.3-155.1° C.; R_(f)=0.10(80% EtOAc/hexanes, 1% MeOH, 1% Et₃N); ¹H NMR (300 MHz, CDCl₃) δ 7.26(d, J=5.7 Hz, 1H), 7.22-7.17 (m, 1H), 7.04-6.96 (comp, 2H), 6.86 (dt,J=2.1, 7.8 Hz, 1H), 6.78 (d, J=5.7 Hz, 1H), 4.28-4.19 (m, 1H), 4.14-4.06(m, 1H), 3.77 (q, J=7.2 Hz, 2H), 3.37 (d, J=8.7 Hz, 1H), 3.23 (d, J=11.1Hz, 1H), 2.98-2.96 (m, 1H), 2.83 (dt, J=4.2, 12.0 Hz, 1H), 2.70 (t,J=7.2 Hz, 2H), 2.62-2.49 (comp, 2H), 2.24 (dt, J=3.0, 11.4 Hz, 1H), 1.82(dd, J=3.3, 9.9 Hz, 1H), 0.97 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃)δ 172.2, 161.3 (d, J=242.8 Hz), 158.9, 152.3, 149.9, 146.1, 146.0,129.4, 129.3, 123.3, 116.0, 114.6 (d, J=21.2 Hz), 112.9 (d, J=20.6 Hz),60.0, 56.8, 55.4, 53.5, 46.2, 41.7, 38.1, 26.7, 14.0; Anal. Calcd forC₂₂H₂₄FN₃O₄S: C, 59.31; H, 5.43; N, 9.43; S, 7.20; F, 4.26; Found: C,59.06; H, 5.52; N, 9.23; S, 7.05; F, 4.06; MS (APCI, [M+H]⁺, m/z) 446.1.

Example 156 Synthesis of (±) syn-ethyl1-(2-(2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)ethyl)-4-(4-(trifluoromethyl)phenyl)piperidine-3-carboxylate(Compound 7c)

Compound 7c was prepared from 4f and 1b as a white solid (142 mg, 52%)using the method of Example 153 above. mp=190.3-191.5° C.; R_(f)=0.10(80% EtOAc/hexanes, 1% MeOH, 1% Et₃N); ¹H NMR (300 MHz, CDCl₃) δ 7.50(d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.26 (d, J=5.7 Hz, 1H), 6.77(d, J=5.7 Hz, 1H), 4.31-4.21 (m, 1H), 4.15-4.07 (m, 1H), 3.75 (q, J=7.2Hz,2H), 3.40 (d, J=9.3 Hz, 1H), 3.27 (d, J=11.4 Hz, 1H), 3.01 (d, J=3.3Hz, 1H), 2.92-2.85 (m, 1H), 2.75-2.66 (m, 2H), 2.63-2.58 (comp, 2H),2.26 (dt, J=2.7, 11.1 Hz, 1H), 1.85 (dd, J=2.7, 12.6 Hz, 1H), 0.95 (t,J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.0, 158.8, 152.1, 149.6,147.6, 128.4 (q, J=32.1 Hz), 128.0, 125.0, 124.4 (q, J=269.7 Hz), 123.4,116.1, 116.0, 60.0, 57.1, 55.3, 53.6, 46.3, 42.0, 38.1, 26.5, 13.9;Anal. Calcd for C₂₃H₂₄F₃N₃O₄S: C, 55.75; H, 4.88; N, 8.48; S, 6.47; F,11.50; Found: C, 55.36; H, 4.97; N, 8.34; S, 6.27; F, 11.21; MS (APCI,[M+H]⁺, m/z) 496.1.

Example 157 Synthesis of syn-ethyl1-(2-(2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)piperidine-3-carboxylate(Compound 7d)

Compound 7d was prepared from 5g and 1b as a white solid (150 mg, 60%)using the method of Example 153 above. mp=153.5-156.5° C.; R_(f)=0.10(80% EtOAc/hexanes, 1% MeOH, 1% Et₃N); ¹H NMR (300 MHz, CDCl₃) δ7.50-7.36 (comp, 4H), 7.26 (d, J=5.4 Hz, 1H), 6.78 (d, J=5.4 Hz, 1H),4.30-4.21 (m, 1H), 4.14-4.06 (m, 1H), 3.76 (q, J=7.2 Hz, 2H), 3.40 (d,J=11.1 Hz, 1H), 3.27 (d, J=11.7 Hz, 1H), 2.99 (d, J=3.6 Hz, 1H), 2.87(dt, J=3.9, 11.7 Hz, 1H), 2.74-2.67 (m, 2H), 2.64-2.54 (comp, 2H), 2.24(dt, J=2.7, 11.4 Hz,1H), 1.85 (d, J=12.9 Hz, 1H), 0.95 (t, J=7.2 Hz,3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.1, 158.8, 152.2, 149.6, 144.4, 131.1,130.3 (q, J=31.5 Hz), 128.5, 124.5, 124.4 (q, J=270.2 Hz), 123.4, 123.0,116.1, 116.0, 60.0, 57.0, 55.3, 53.6, 46.3, 42.0, 38.1, 26.6, 13.9;Anal. Calcd for C₂₃H₂₄F₃N₃O₄S: C, 55.75; H, 4.88; N, 8.48; S, 6.47; F,11.50; Found: C, 56.01; H, 4.98; N, 8.37; S, 6.24; F, 11.26; MS (APCI,[M+H]⁺, m/z) 496.1.

Example 158 Synthesis of (±) syn-ethyl4-(4-fluorophenyl)-1-(2-(1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)ethyl)piperidine-3-carboxylate(Compound 8a)

Compound 8a was prepared from 7a as a white solid (46 mg, 83%) using themethod of Example 147 above. mp=132.5-133.8° C.; Rf=0.25 (80%EtOAc/hexanes, 1% Et₃N, 1% MeOH); ¹H NMR (300 MHz, CDCl₃) δ 7.34 (d,J=5.7 Hz, 1H), 7.24 (dd, J=3.0, 5.4 Hz, 2H), 6.83 (d, J=5.7 Hz, 1H),4.27-4.07 (m, 2H), 3.74 (dq, J=1.8, 7.2 Hz, 2H), 3.57 (s, 3H), 3.34 (d,J=9.9 Hz, 1H), 3.21 (d, J=10.5 Hz, 1H), 2.9 (q, J=3.3 Hz, 1H), 2.77 (dt,J=3.6, 11.7 Hz, 1H), 2.67-2.60 (comp, 2H), 2.58-2.50 (comp, 2H), 2.22(dt, J=2.4, 11.1 Hz, 1H), 1.78 (dd, J=3.3, 12.9 Hz, 1H), 0.98 (t, J=7.2Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 171.9, 161.3 (d, J=241.6 Hz), 158.4,153.6, 151.1, 139.2, 129.1 (d, J=7.4 Hz), 124.7, 115.8, 115.6, 114.7 (d,J=21.2 Hz), 59.6, 57.0, 55.3, 53.8, 46.5, 41.7, 38.9, 35.0, 26.8, 14.0;Anal. Calcd for C₂₃H₂₆FN₃O₄S: C, 60.11; H, 5.70; N, 9.14; S, 6.98;Found: C, 59.88; H, 5.83; N, 8.89; S, 6.98; MS (APCI, [M+H]⁺, m/z)460.2.

Example 159 Synthesis of (±)-syn-Methyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate (Compound 10a)

Compound 10a was synthesized according to Scheme 1 above in 67% yield.MP(HCl)=191.5-193° C. ¹H NMR (300 MHz, CDCl₃) δ 9.20 (s, 1H), 8.12 (d,J=7.98 Hz, 1H), 7.58 (td, J=1.4, 7.7 Hz, 1H), 7.24-7.15 (m, 4H), 7.04(d, J=8.3 Hz, 1H), 6.93 (t, J=8.7 Hz, 2H), 4.35-4.07 (m, 2H), 3.37 (dd,J=2.9, 12.2 Hz, 1H), 3.28 (s, 3H), 3.26-3.16 (m, 1H), 2.93 (q, J=3.8 Hz,1H), 2.86-2.74 (m, 1H), 2.74-2.65 (m, 2H), 2.62-2.49 (m, 2H), 2.24 (td,J=2.6, 11.1 Hz, 1H), 1.77 (dd, J=3.0, 12.7 Hz, 1H). ¹³C NMR (75 MHz,CDCl₃) δ 172.4, 162.3, 151.4, 139.0, 139.0, 138.5, 135.0, 129.2, 129.1,128.6, 123.4, 115.0, 114.8, 114.7, 56.8, 55.3, 53.9, 50.9, 46.6, 41.7,38.2, 26.8. Anal. (C₂₃H₂₄FN₃O₄; 1.2 HCl; 1.5 H₂O) C, H, N, Cl.

Example 160 Synthesis of (±)-syn-Isopropyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H),-yl)ethyl)-4-(4-fluorophenyl)piperidine-3-carboxylate(Compound 10b)

Compound 10b was synthesized as described in Scheme 1 above in 60%yield. MP (HCl)=157.5-159° C. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.42 (br.s., 1H), 8.11 (d, J=8.0 Hz, 1H), 7.59 (td, J=7.6, 1.1 Hz, 5H), 7.24-7.17(m, 3H), 7.05 (d, J=8.0 Hz, 1H), 6.93 (t, J=8.8 Hz, 2H), 4.67 (quin,J=6.3 Hz, 1H), 4.36-4.21 (m, 1H), 4.15 (dt, J=12.8, 6.5 Hz, 1H), 3.34(d, J=11.8 Hz, 1H), 3.22 (d, J=9.9 Hz, 1H), 2.94-2.76 (m, 2H), 2.69 (t,J=6.6 Hz, 2H), 2.57 (dd, J=11.6, 3.0 Hz, 2H), 2.25 (td, J=10.8, 2.3 Hz,1H), 1.80 (d, J=10.2 Hz, 1H), 0.93 (d, J=2.8 Hz, 3H), 0.91 (d, J=2.5 Hz,3H). ¹³C NMR (75 MHz, CDCl₃) δ 171.6, 162.4, 151.5, 138.6, 135.0, 129.2,129.1, 128.5, 123.4, 114.8, 114.8, 114.7, 114.6, 67.0, 56.9, 55.4, 53.7,46.5, 41.4, 38.3, 21.7, 21.5. Anal. (C₂₅H₂₈FN₃O₄.2HCl) C, H, N.

Example 161 Synthesis of Compound 12

Compound 12 was synthesized according to Scheme 2:

Example 162 Synthesis of Ethyl4-(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (Compound11)

A round bottomed flask was charged with 3d (845 mg, 2.5 mmol), thenα-chloroethyl chloroformate (ACE-Cl, 2.96 mL, 27.4 mmol) was added undernitrogen by syringe in one portion, and the reaction mixture stirred for2 h at 100° C. Volatiles were removed in vacuo and the residue wastreated with anhydrous EtOH (8.3 mL). The flask was then heated toreflux for 20 min and concentrated in vacuo. The solid residue waspurified by flash chromatography using 0-10% MeOH/EtOAc (1% i-PrNH₂) togive 11 as a yellow oil (538 mg, 87%): R_(f)=0.22 (10% MeOH/CH₂Cl₂); ¹HNMR (300 MHz, CDCl₃) δ 7.10 (dd, J=5.50, 8.81 Hz, 2H), 6.99 (t, J=8.81Hz, 2H), 3.91 (q, J=7.15 Hz, 2H), 3.67 (t, J=2.75 Hz, 2H), 3.05 (t,J=5.78 Hz, 2H), 2.38 (spt, J=2.75 Hz, 2H), 0.91 (t, J=6.88 Hz, 3H).

Example 163 Synthesis of Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4-(4-fluorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate(Compound 12)

Compound 12 was prepared from 11 and 1a as a white solid (95 mg, 30%)using Scheme 2 above. mp=150-152° C. (Dec.); R_(f)=0.56 (10%MeOH/CH₂Cl₂); ¹H NMR (301 MHz, CDCl₃) δ 10.31 (s, 1H), 8.09 (d, J=7.6Hz, 1H), 7.60 (ddd, J=1.1, 7.2, 8.3 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H),7.04-7.14 (m, 3H), 6.98 (t, J=8.8 Hz, 2H), 4.34 (t, J=6.9 Hz, 2H), 3.93(q, J=7.2 Hz, 2H), 3.50 (br. s., 2H), 2.89 (m, 4H), 2.53 (br. s., 2H),0.93 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 167.4, 163.6, 162.5,160.4, 150.7, 144.5, 140.0, 138.5, 135.6, 129.5, 129.4, 127.9, 126.2,123.1, 115.7, 115.4, 115.2, 114.3, 60.3, 54.7, 53.5, 49.6, 38.1, 33.1,14.0; Anal. Calcd for C₂₄H₂₄N₃O₄F.1/2H₂O: C, 64.56; H, 5.64; N, 9.41; F,4.26; Found: C, 64.34; H, 5.40; N, 9.23; F, 4.39; MS (APCI, [M+H]⁺, m/z)438.2.

Example 164 Synthesis of Compounds 16 and 18

Compounds 16 and 18 were synthesized according to Scheme 3

Example 165 Synthesis of3-(2-(4-(4-fluorophenyl)piperidin-1-yl)ethyl)quinazoline-2,4(1H,3H)-dione(Compound 16)

Compound 16 was prepared from 15 and 1a as a light-brown solid (170 mg,86%) using Scheme 3 above. mp=263.0-264.0° C.; ¹H NMR (300 MHz, DMSO-d₆)δ 11.44 (s, 1H), 7.93 (dd, J=1.0, 8.0 Hz, 1H), 7.65 (td, J=1.0, 7.7 Hz,1H), 7.13-7.34 (m, 4H), 7.08 (t, J=8.8 Hz, 2H), 4.04 (t, J=7.2 Hz, 2H),3.03 (d, J=11.0 Hz, 2H), 2.31-2.64 (m, 3H), 2.07 (t, J=11.0 Hz, 2H),1.64-1.82 (m, 2H), 1.44-1.64 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 162.8,162.4, 161.1, 150.7, 143.0, 140.0, 135.5, 129.0, 128.9, 127.9, 123.1,115.6, 115.3, 114.3, 55.8, 54.4, 41.5, 38.2, 33.8; Anal. Calcd forC₂₁H₂₂N₃O₂F: C, 68.65; H, 6.04; N, 11.44; F, 5.17; Found: C, 68.36; H,6.13; N, 11.04; F, 4.83; MS (APCI, [M+H]⁺, m/z) 368.2.

Example 166 Synthesis of3-(2-(4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl)ethyl)quinazoline-2,4(1H,3H)-dione(Compound 18)

Compound 18 was prepared from 17 and 1a as a white solid (189 mg, 52%)using Scheme 3 above. mp=208.0° C. (Dec.); R_(f)=0.20 (10% MeOH/CH₂Cl₂);¹H NMR (300 MHz, DMSO-d₆) δ 11.44 (br. s, 1H), 7.93 (d, J=8.0 Hz, 1H),7.65 (t, J=7.7 Hz, 1H), 7.45 (dd, J=5.5, 8.8 Hz, 2H), 7.21 (d, J=7.7 Hz,1H), 7.17 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.8 Hz, 2H), 5.97-6.19 (m, 1H),4.09 (t, J=6.9 Hz, 2H), 3.16 (d, J=2.5 Hz, 2H), 2.71 (t, J=5.5 Hz, 2H),2.64 (t, J=6.9 Hz, 2H), 2.32-2.47 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ163.5, 162.5, 160.3, 150.7, 140.0, 137.1, 135.5, 133.5, 127.9, 127.0,126.9, 123.1, 122.6, 115.7 (2 signals), 115.5, 114.3, 55.2, 53.4, 50.3,38.1, 28.0; Anal. Calcd for C₂₁H₂₀N₃O₂F: C, 69.03; H, 5.52; N, 11.50; F,5.20; Found: C, 68.79; H, 5.47; N, 11.35; F, 5.11; MS (APCI, [M+H]⁺,m/z) 366.2.

Example 167 Synthesis of Compounds of Series 23

Compounds of Series 23 were prepared according to Scheme 4:

Example 168 Synthesis of 1-tert-butyl 3α-ethyl4α-(4-fluorophenyl)piperidine-1,3-dicarboxylate (Compound 20d)

A 50 mL round bottomed flask was charged with 5d (215 mg, 0.86 mmol),MeOH (5mL), triethylamine (240 uL, 1.72 mmol) and a magnetic stir bar.Boc₂O (375 mg, 1.72 mmol) was added with vigorous stirring and themixture was heated to 60° C. for 30 min. Volatiles were removed in vacuoand the residue was partitioned between CH₂Cl₂ (15 mL) and brine (5 mL).The layers were separated, and the aqueous layer was further extractedwith CH₂Cl₂ (2×10 mL). The combined organic layers were dried (MgSO₄),filtered, and concentrated, then purified by flash chromatographyeluting with 0-100% EtOAc/hexanes to give 20d (214 mg, 71%): R_(f)=0.75(50% EtOAc/hexanes, 1% Et₃N); ¹H NMR (300 MHz, CDCl₃) δ 7.19 (dd, J=5.5,8.8 Hz, 1H), 6.95 (t, J=8.8 Hz, 2H), 4.09-4.64 (m, 2H), 3.92 (q, J=7.2Hz, 2H), 3.01-3.29 (m, 1H), 2.71-3.02 (m, 2H), 2.48-2.71 (m, 1H),1.54-1.85 (m, 2H), 1.47 (s, 9H), 1.04 (t, J=7.2 Hz, 3H); ¹³C NMR (75MHz, CDCl₃) δ 171.6, 163.3, 160.0, 154.5, 138.3, 129.1, 129.0, 115.2,115.0, 79.7, 60.2, 49.1, 45.7, 43.6, 42.5, 28.5, 25.9, 14.1.

Example 169 Synthesis of 1-tert-butyl 3β-ethyl4α-(4-fluorophenyl)piperidine-1,3-dicarboxylate (Compound 21d)

A 50 mL round bottomed flask was charged with 20d (194 mg, 0.55 mmol),EtOH (5 mL), and NaOEt (56 mg, 0.83 mmol), then heated to 70° C. for 3 hin an oil bath. The solution was concentrated in vacuo and purified byflash chromatography eluting with 0-30% EtOAc/hexanes to give pure(trans) 21d (137 mg, 71%): R_(f)=0.87 (50% EtOAc/hexanes, +1% Et₃N); ¹HNMR (300 MHz, CDCl₃) δ 7.13 (dd, J=5.2, 8.8 Hz, 2H), 6.96 (t, J=8.8 Hz,2H), 4.35 (br. s, 1H), 4.24 (br. s., 1H), 3.89 (q, J=7.2 Hz, 2H),2.72-3.04 (m, 3H), 2.47-2.71 (m, 1H), 1.69-1.87 (m, 1H), 1.56-1.69 (m,H), 1.48 (s, 9H), 0.95 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ172.5, 163.4, 160.2, 154.5, 138.6, 129.0, 128.9, 115.5, 115.2, 80.2,60.4, 49.1, 46.3, 45.1, 44.1, 32.9, 28.5, 14.0.

Example 170 Synthesis of Ethyl4α-(4-fluorophenyl)piperidine-3β-carboxylate (Compound 22d)

Compound 21d (126 mg, 0.36 mmol) was taken up in HCl (4M in dioxane, 6.3mL) under N₂. The solution was stirred 45 min, and neutralized withsolid NaHCO₃ (4.60 g). The reaction mixture was diluted with water (20mL), and extracted with CH₂Cl₂ (3×20 mL). The combined organic layerswere dried (MgSO₄), concentrated. The residue was purified by flashchromatography eluting with 0-10%MeOH/CH₂Cl₂ (1% Et₃N) to give 22d (90mg, 100%); ¹H NMR (300 MHz, CDCl₃) δ 7.15 (dd, J=5.2, 8.8 Hz, 2H), 6.94(t, J=8.8 Hz, 2H), 3.87 (q, J=7.2 Hz, 2H), 3.33 (dd, J=3.6, 11.8 Hz,1H), 3.10-3.25 (m, 1H), 2.62-2.95 (m, 4H), 2.25 (br. s, 1H), 1.74-1.92(m, 1H), 1.62 (dq, J=4.1, 12.6 Hz, 1H), 0.95 (t, J=7.2 Hz, 3H).

Example 171 Synthesis of Ethyl1-(2-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)ethyl)-4α-(4-fluorophenyl)piperidine-3β-carboxylate (Compound 23d)

Compound 23d was prepared from 22d and 1a as an off-white solid (68 mg,47%) using the general procedure described above. mp=195.0-197.0° C.;R_(f)=0.54 (10% MeOH/CH₂Cl₂); ¹H NMR (300 MHz, DMSO-d₆) δ 11.47 (s, 1H),7.94 (dd, J=1.1, 8.0 Hz, 1H), 7.66 (ddd, J=1.4, 7.4, 8.0 Hz, 1H),7.14-7.30 (m, 4H), 7.07 (t, J=8.8 Hz, 2H), 4.04 (t, J=6.9 Hz, 2H), 3.82(qd, J=1.7, 7.2 Hz, 2H), 3.18 (d, J=10.7 Hz, 1H), 3.02 (d, J=10.7 Hz,1H), 2.65-2.78 (m, 2H), 2.60 (t, J=6.9 Hz, 2H), 2.07-2.27 (m, 2H),1.51-1.75 (m, 2H), 0.87 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ172.9, 163.0, 162.5, 159.8, 150.7, 140.2, 140.0, 135.6, 129.7, 129.6,127.9, 123.1, 115.7, 115.6, 115.3, 114.3, 60.1, 56.2, 55.2, 53.9, 49.1,44.7, 38.0, 33.3, 14.3; Anal. Calcd for C₂₄H₂₆N₃O₄F: C, 65.59; H, 5.96;N, 9.56; F, 4.32; Found: C, 65.52; H, 6.09; N, 9.42; F, 4.24; MS (APCI,[M+H]⁺, m/z) 440.2.

Example 172 Synthesis of 1-methylquinazoline-2,4(1H,3H)-dione

To a stirred mixture of Methyl N-Methyl anthranilate (1.46 mL, 10 mmol)in glacial acetic acid (10 mL) was added KOCN (975 mg, 12 mmol) in 3 mLof H₂O. The solution was stirred at room temperature overnight and thenheated to 70° C. for 3 hours. The reaction was cooled to 0° C. and thenfiltered. The white solid was washed with cold ethanol and dried. Theproduct was collected as a white solid (1.46 g) in 80% yield. ¹H NMR(300 MHz, DMSO-d₆) δ 11.53 (br. s., 1H), 7.97 (d, J=7.71 Hz, 1H),7.88-7.64 (m, 1H), 7.38 (d, J=8.81 Hz, 1H), 7.25 (t, J=7.57 Hz, 1H) 3.42(s, 3H).

Example 173 Synthesis of3-(2-hydroxyethyl)-1-methylquinazoline-2,4(1H,3H)-dione

To a stirred solution of 1-methylquinazoline-2,4(1H,3H)-dione (1.40 g,7.95 mmol) and K₂CO₃ (2.2 g, 15.9 mmol) in dry DMF (10 mL) under apositive stream of nitrogen was added 2-Bromoethanol (0.62 mL, 8.75mmol). The solution was heated to 90° C. for 3 hours. The reactionmixture was cooled to room temperature, filtered and concentrated. Thecrude oil was diluted with EtOAc (20 mL) and washed with brine (3×50mL). The organic layer was dried over Na₂SO₄ and concentrated to providethe title compound (1.13 g) in 65% yield. ¹H NMR (300 MHz, DMSO-d₆)□8.03 (dd, J=1.65, 7.98 Hz, 1H), 7.76 (ddd, J=1.65, 7.09, 8.60 Hz, 1H),7.43 (d, J=8.26 Hz, 1H), 7.28 (t, J=7.57 Hz, 1H), 4.76 (t, J=6.05, Hz,1H), 4.03 (t, J=6.60 Hz, 2H), 3.55 (q, J=6.51 Hz, 2H), 3.50 (s, 3H).

Example 174 Synthesis of2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)acetaldehyde(Compound SM B)

To a solution of 3-(2-hydroxyethyl)-1-methylquinazoline-2,4(1H,3H)-dione(500 mg, 2.27 mmol) in dry CH₂Cl₂ was added Dess-Martin periodirane(1.45 g, 3.41 mmol) under a positive stream of N₂. The solution wasstirred overnight at room temperature. The reaction was then quenched bythe addition of an aqueous sat. NaHCO₃ solution and extracted withCH₂Cl₂ (3×20 mL). The combined organic extracts were dried over Na₂SO₄and concentrated. The crude product was purified on a silica gel column(50-100% EtOAc/Hexanes) to give pure title compound (410 mg) in 83%yield. ¹H NMR (300 MHz, DMSO-d₆) δ 9.60 (s, 1H), 8.05 (dd, J=1.65, 7.71Hz, 1H), 7.82 (ddd, J=1.79, 7.15, 8.67 Hz, 1H), 7.50 (d, J=8.26 Hz, 1H),7.40-7.27 (m, 1H), 4.82 (s, 2H), 3.53 (s, 3H).

Example 175 Synthesis of-(2-(4-(4-fluorophenyl)-3-propionyl-5,6-dihydropyridin-1(2H)-yl)ethyl)-1-methylquinazoline-2,4(1H,3H)-dione

To a dry 25 mL round bottomed flask under a nitrogen atmosphere wasadded SM A (25 mg, 0.107 mmol) and SM B (25.6 mg, 0.118 mmol) followedby dry MeOH (2 mL). NaCNBH₃ (8.1 mg, 0.128 mmol) was then added to thesolution and the mixture was heated to 50° C. for 2 hours. The solutionwas diluted with CH₂Cl₂ and the organic layer was washed with brine. Theorganic layer was dried over Na₂SO₄ and concentrated. The crude productwas purified on a silica gel column (50-100% EtOAc/Hexanes) to providethe title compound as a white solid (45.4 mg) in 97% yield. ¹H NMR (300MHz, CDCl₃) δ 8.20 (dd, J=1.79, 7.84 Hz, 1H), 7.67 (ddd, J=1.65, 7.09,8.60 Hz, 1H), 2.28-7.16 (m, 2H), 7.16-7.06 (m, 2H), 7.00 (t, J=8.67 Hz,2H), 4.31(t, J=6.88, 6.88 Hz, 2H), 3.59 (s, 3H), 3.35 (t, J=2.61 Hz,2H), 2.74-2.90 (m, 4H), 2.53 (sept., J=3.03 Hz, 2H), 1.96 (q, J=7.25 Hz,2H), 0.79 (t, J=7.29 Hz, 3H).

All documents, including patents, patent application and publicationscited herein, including all documents cited therein, tables, anddrawings, are hereby expressly incorporated by reference in theirentirety for all purposes.

While the foregoing written description of the compounds, uses, andmethods described herein enables one of ordinary skill in the art tomake and use the compounds, uses, and methods described herein, those ofordinary skill in the art will understand and appreciate the existenceof variations, combinations, and equivalents of the specific embodiment,method, and examples herein. The compounds, uses, and methods providedherein should therefore not be limited by the above-describedembodiments, methods, or examples, but rather encompasses allembodiments and methods within the scope and spirit of the compounds,uses, and methods provided herein.

1-48. (canceled)
 49. A compound with the formula:

wherein X is a substituted or unsubstituted 5- or 6-membered aryl orsubstituted or unsubstituted 5- or 6-membered heteroaryl, Z is N or CH,m is 1, 2, or 3, Ar is a substituted or unsubstituted 5- or 6-memberedaryl or a substituted or unsubstituted 5- or 6-membered heteroaryl, R isH, ethyl ester, isopropyl ester, —C(O)-alkyl, or substituted orunsubstituted 5-membered heteroaryl, Y is H, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted heteroaryl; or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer, mixture of stereoisomers, crystal form,or isotopomer thereof.
 50. The compound of claim 49, wherein R is ethylester or —C(O)-alkyl.
 51. The compound of claim 49, wherein Ar isphenyl, substituted phenyl, pyrrolyl, substituted pyrrolyl, pyridinyl,substituted pyridinyl, thiophene-yl, substituted thiophene-yl, or[1,4]-dioxinyl.
 52. The compound of claim 49, wherein the structure ofthe compound is:

wherein A₁, A₂, A₃, and A₄, are independently H, alkyl, substitutedalkyl, aryl, substituted aryl, halo, alkoxy, haloalkyl, haloalkoxy,ester, keto, hydroxyl, amino, substituted amino, amido, nitro, methyl,ethyl, isopropyl, [1,4]dioxin-5-yl, fluoro, chloro, trifluoromethyl,amino, dimethylamino, methylamido, azo, benzyl, 2-phenyl ethyl,pyrrolyl, ethyl ester, 1-hydroxyethyl, methoxy, trifluoromethoxy, ortert-butoxycarbonylamino.
 53. The compound of claim 52, wherein A₁ andA₂ are H, and A₃ and A₄ are independently H, fluoro, or trifluoromethyl.54. The compound of claim 49, wherein the structure of the compound is:

and wherein A₃ is halo or fluoro, and m is 2 or
 3. 55. The compound ofclaim 49, wherein the structure of the compound is:

wherein Y₁ is H, methyl, ethyl, or 2-benzylethyl, wherein Y₂ is H orhalo, and wherein A₃ and A₄ are independently H or halo.
 56. Thecompound of claim 49, wherein the structure of the compound is:

wherein A₁, A₂, A₃, and A₄ are independently H, halo, or haloalkyl, andwherein Y is H or alkyl.
 57. The compound of claim 56, wherein Y is H,A₁ and A₂ are H, and A₃ and A₄ are independently H, fluoro, ortrifluoromethyl.
 58. A compound of the Formula I:

wherein X is a substituted or unsubstituted 5- or 6-membered aryl orsubstituted or unsubstituted 5- or 6-membered heteroaryl, Z is N or CH,m is 1, 2, or 3, Ar is a substituted or unsubstituted 5- or 6-memberedaryl or a substituted or unsubstituted 5- or 6-membered heteroaryl, R isethyl ester, isopropyl ester, —C(O)-alkyl, or substituted orunsubstituted 5-membered heteroaryl, Y is H, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted heteroaryl; wherein the bond between the carbon atomsbearing Ar and R is a single or double bond, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, mixture ofstereoisomers, crystal form, or isotopomer thereof.
 59. The compound ofclaim 58, wherein R is ethyl ester or —C(O)-alkyl.
 60. The compound ofclaim 58, wherein Ar is phenyl, substituted phenyl, pyrrolyl,substituted pyrrolyl, pyridinyl, substituted pyridinyl, thiophene-yl,substituted thiophene-yl, or [1,4]-dioxinyl.
 61. The compound of claim58, wherein the structure of the compound is:

wherein A₁, A₂, A₃, and A₄, are independently H, alkyl, substitutedalkyl, aryl, substituted aryl, halo, alkoxy, haloalkyl, haloalkoxy,ester, keto, hydroxyl, amino, substituted amino, amido, nitro, methyl,ethyl, isopropyl, [1,4]dioxin-5-yl, fluoro, chloro, trifluoromethyl,amino, dimethylamino, methylamido, azo, benzyl, 2-phenyl ethyl,pyrrolyl, ethyl ester, 1-hydroxyethyl, methoxy, trifluoromethoxy, ortert-butoxycarbonylamino.
 62. The compound of claim 61, wherein A₁ andA₂ are H, and A₃ and A₄ are independently H, fluoro, or trifluoromethyl.63. The compound of claim 58, wherein the structure of the compound is:

wherein A₃ is halo or fluoro, and m is 2 or
 3. 64. The compound of claim58, wherein the structure of the compound is:

wherein Y₁ is H, methyl, ethyl, or 2-benzylethyl, wherein Y₂ is H orhalo, and wherein A₃ and A₄ are independently H or halo.
 65. Thecompound of claim 58, wherein the structure of the compound is:

wherein A₁, A₂, A₃, and A₄ are independently H, halo, or haloalkyl, andwherein Y is H or alkyl.
 66. The compound of claim 65, wherein Y is H,A₁ and A₂ are H, and A₃ and A₄ are independently H, fluoro, ortrifluoromethyl.
 67. The compound of claim 58, wherein the structure ofthe compound is:


68. A method for treating a subject having a methamphetamine (MA)addiction, comprising: Administering to the subject a therapeuticallyeffective amount of a pharamaceutical composition comprising compoundwith the formula:

wherein X is a substituted or unsubstituted 5- or 6-membered aryl orsubstituted or unsubstituted 5- or 6-membered heteroaryl, Z is N or CH,m is 1, 2, or 3, Ar is a substituted or unsubstituted 5- or 6-memberedaryl or a substituted or unsubstituted 5- or 6-membered heteroaryl, R isethyl ester, isopropyl ester, —C(O)-alkyl, or substituted orunsubstituted 5-membered heteroaryl, Y is H, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, or substitutedor unsubstituted heteroaryl; wherein the bond between the carbon atomsbearing Ar and R is a single or double bond, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer, mixture ofstereoisomers, crystal form, or isotopomer thereof.